Therapeutic amides

ABSTRACT

Amides having formula I: ##STR1## wherein E, X, R 2  and R 3  have the meanings given in the specification, and pharmaceutically acceptable salts and pharmaceutically acceptable in vivo hydrolysable esters thereof, which are useful in the treatment of urinary incontinence. Further provided are processes for preparing the aides and pharmaceutical compositions containing them.

This is a divisional of application Ser. No. 08/329,188 filed on Oct.26, 1994, now U.S. Pat. No. 5,414,999; which is a divisional of U.S.application Ser. No. 08/126,350, filed 24 Sep. 1993, now U.S. Pat. No.5,382,598; which is a divisional of U.S. application Ser. No.07/918,982, filed 23 Jul. 1992, now U.S. Pat. No. 5,272,163.

This invention relates to compounds useful as cell potassium channelopeners in mammals such as-man. More specifically, the invention relatesto certain substituted amides which are useful in the treatment ofurinary incontinence in mammals. Because compounds according to theinvention function to open cell potassium channels, they may also beuseful as therapeutic agents in the treatment of conditions or diseasesin which the action of a therapeutic agent which opens potassiumchannels is desired or is known to provide amelioration. Such conditionsor diseases include hypertension, asthma, peripheral vascular disease,right heart failure, congestive heart failure, angina, ischemic heartdisease, cerebrovascular disease, renal cholic, disorders associatedwith kidney stones, irritable bowel syndrome, male pattern baldness,premature labor, impotence, and peptic ulcers.

Treatment using a compound of the invention can be remedial ortherapeutic as by administering a compound following the onset ordevelopment of urinary incontinence in a patient. Treatment can also beprophylactic or prospective by administering a compound in anticipationthat urinary incontinence may develop, for example in a patient who hassuffered from incontinence in the past.

It is known that bladder tissue is excitable and that urinaryincontinence can be caused by uncontrolled or unstable bladdercontractions. It is further known that by functioning to open potassiumchannels, potassium channel opening compounds can thereby function torelax smooth muscle. While not wishing to be bound by theory, it isaccordingly believed that the compounds of this invention function byopening potassium channels in bladder cells and thereby relax bladdersmooth muscle tissue, thus preventing or ameliorating uncontrolledbladder contractions which can cause urinary incontinence.

This invention provides an amide having formula I (formula set out,together with other formulae referred to in the specification by Romannumerals, on pages following the Examples), wherein:

E is selected from nitrogen and CZ wherein C is a ring carbon and Z is asubstituent defined below, wherein:

when E is CZ, X and Z are selected from the group consisting of:

(A) X is ArY wherein Y is a linking group selected from carbonyl,sulfinyl, and sulfonyl and Ar is selected from the group consisting of:

phenyl substituted with 0-2 substituents selected from halo, hydroxy,cyano, (1-4C)alkyl, and (1-4C)alkoxy, provide that the 4-position ofsaid phenyl may be substituted by fluoro only, and that the said phenylmay not be 3,5-disubstituted;

six-membered heteroaryl rings containing 1-2 nitrogen atoms as the onlyheteroatoms;

five-membered heteroaryl rings containing from 1-2 heteroatoms selectedfrom nitrogen, oxygen, and sulfur; provided that Ar is not3-chlorophenyl, 3-bromophenyl, 3-iodophenyl, 3-(1-4C)alkylphenyl, or4-pyridyl when Y is carbonyl, and that Ar is not 5-pyrimidinyl when Y issulfonyl or carbonyl; and

Z is selected from hydrogen, cyano, halo, hydroxy, (1-4C)alkyl, and(1-4C)alkoxy;

(B) X is cyano and Z is selected from the group consisting ofphenylthio, phenylsulfinyl, and phenylsulfonyl the phenyl rings of whichare substituted with 0-2 substituents selected from halo, hydroxy,cyano, nitro, (1-4C)alkyl, and (1-4C)alkoxy;

when E is nitrogen, X is independently selected from any of the valuesfor X given above in (A);

R² and R³

are independently selected from the group consisting of (1-3C)alkylsubstituted by from 0 to 2k+1 groups selected from fluoro and chlorowherein k is the number of carbon atoms in the said (1-3C)alkyl,provided that R² and R³ are not both methyl; or

together, with the carbon atom to which both R² and R³ are attached,form a 3-5 membered cycloalkyl ring optionally substituted by from 0 to2m-2 fluoro groups wherein m is the number of carbon atoms in said ring;

and pharmaceutically acceptable in vivo hydrolyzable esters of saidamide;

and pharmaceutically acceptable salts of said amides and said esters.

The invention further provides a method for the treatment of urinaryincontinence, comprising administering to a mammal (including man) inneed of such treatment an effective amount of an amide of formula I asdefined above, or a pharmaceutically acceptable in vivo hydrolyzableester or pharmaceutically acceptable salt thereof.

The invention further provides a pharmaceutical composition suitable forthe treatment of urinary incontinence comprising an amide of formula Ias defined above, or a pharmaceutically acceptable in vivo hydrolyzableester or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable diluent or carrier.

In this specification the terms "alkyl" and "alkoxy" include bothstraight and branched chain radicals, but it is to be understood thatreferences to individual radicals such as "propyl" or "propoxy" embraceonly the straight chain ("normal") radical, branched chain isomers suchas "isopropyl" or "isopropoxy" being referred to specifically.

The term "halo" is inclusive of fluoro, chloro, bromo, and iodo unlessnoted otherwise.

It will be appreciated by those skilled in the art that certaincompounds of formula I contain an asymmetrically substituted carbonand/or sulfur atom, and accordingly may exist in, and be isolated in,optically-active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic or stereoisomericform; or mixtures thereof, which form possesses properties useful in thetreatment of urinary incontinence, it being well known in the art how toprepare optically-active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase) and how todetermine efficacy for the treatment of urinary incontinence by thestandard tests described hereinafter.

Particular values of Ar as phenyl substituted with 0-2 substitutentsinclude phenyl, 2- and 3-halophenyl, 4-fluorophenyl, 2-, and3-hydroxyphenyl, 2-, and 3-cyanophenyl, 2- and 3-methylphenyl, 2- and3-ethylphenyl, 2- and 3-propylphenyl, 2- and 3-methoxyphenyl, 2- and3-ethoxyphenyl, 2- and 3-propoxyphenyl, 2,5-difluorophenyl, and2,3-difluorophenyl.

Particular values of Ar as a six-membered heteroaryl ring containing 1-2nitrogen atoms include 2, 3-, and 4-pyridyl, 2-pyrazinyl, 2- and4-pyrimidinyl, and 3- and 4-pyridazinyl.

Particular values of Ar as a five-membered heteroaryl ring containingfrom 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur include3-, 4- and 5-isothiazolyl, 2-, 4- and 5-oxazolyl, 2-, 4- and5-thiazolyl, 2- and 3-furyl, and 2- and 3-thienyl.

Particular values of Z as (1-4C)alkyl include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Particular values of Z as (1-4C)alkoxy include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

Particular values of Z as phenylthio substituted with from 0-2substitutents include phenylthio, 2-, 3-, and 4-halophenylthio, 2-, 3-,and 4-hydroxyphenylthio, 2-, 3-, and 4-cyanophenylthio, 2-, 3-, and4-methylphenylthio, 2-, 3-, and 4-ethylphenylthio, 2-, 3-, and4-propylphenylthio, 2-, 3-, and 4-methoxyphenylthio, 2-, 3-, and4-ethoxyphenylthio, 2-, 3-, and 4-propoxyphenylthio,2,4-difluorophenylthio, and 2,3-difluorophenylthio.

Particular values of Z as phenylsulfinyl substituted with from 0-2substitutents include phenylsulfinyl, 2-, 3-, and 4-halophenylsulfinyl,2-, 3-, and 4-hydroxyphenylsulfinyl, 2-, 3-, and 4-cyanophenylsulfinyl,2-, 3-, and 4-methylphenylsulfinyl, 2-, 3-, and 4-ethylphenylsulfinyl,2-, 3-, and 4-propylphenylsulfinyl, 2-, 3-, and 4-methoxyphenylsulfinyl,2-, 3-, and 4-ethoxyphenylsulfinyl, 2-, 3-, and 4-propoxyphenylsulfinyl,2,4-difluorophenylsulfinyl, and 2,3-difluorophenylsulfinyl.

Particular values of Z as phenylsulfonyl substituted with from 0-2substitutent include phenylsulfonyl, 2-, 3-, and 4-halophenylsulfonyl,2-, 3-, and 4-hydroxyphenylsulfonyl, 2-, 3-, and 4-cyanophenylsulfonyl,2-, 3-, and 4-methylphenylsulfonyl, 2-, 3-, and 4-ethylphenylsulfonyl,2-, 3-, and 4-propylphenylsulfonyl, 2-, 3- and 4-methoxyphenylsulfonyl,2-, 3-, and 4-ethoxyphenylsulfonyl, 2-, 3-, and 4-propoxyphenylsulfonyl,2,4-difluorophenylsulfonyl, and 2,3-difluorophenylsulfonyl.

Particular values of R2 and R3 as (1-3C)alkyl substituted by from 0 to2k+l groups selected from fluoro and chloro include methyl, ethyl,propyl, isopropyl, chloromethyl, dichloromethyl, chlorodifluoromethyl,trichloromethyl, 1-chloroethyl, 1,1-dichloroethyl, 2-chloroethyl,2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dichloroethyl,1,1,2-trichloroethyl, 1,2,2-trichloroethyl, 1,1,2,2-tetrachloroethyl,1,2,2,2-tetrachloroethyl, 1,1,2,2,2-pentachloroethyl, 1-chloropropyl,1,1-dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl,1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 1,1,2-trifluoroethyl,1,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl,1,2,2,2-tetrafluoroethyl, 1,1,2,2,2-pentafluoroethyl, 1-fluoropropyl,and 1,1-difluoropropyl.

Particular values of 3-5 membered cycloalkyl rings substituted by from 0to 2m-2 fluoro groups, which can be formed by R2 and R3 together withthe carbon atom to which R² and R³ are attached, include cyclopropyl,cyclobutyl, cyclopentyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, 2,2,3-trifluorocyclopropyl,2,2,3,3-tetrafluorocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl,2,3-difluorocyclobutyl, 2,4-difluorocyclobutyl, 2,2-difluorocyclobutyl,2,3,4-trifluorocyclobutyl, 2,3,3-trifluorocyclobutyl,2,2,3-trifluorocyclobutyl, 2,2,4-trifluorocyclobutyl,2,2,3,4-tetrafluorocyclobutyl, 2,3,3,4-tetrafluorocyclobutyl,2,2,3,3-tetrafluorocyclobutyl, 2,2,4,4-tetrafluorocyclobutyl,2,2,3,3,4-pentafluorocyclobutyl, 2,2,3,4,4-pentafluorocyclobutyl,hexafluorocyclobutyl, 2-fluorocyclopentyl, 3-fluorocyclopentyl,2,2-difluorocyclopentyl, 2,3-difluorocyclopentyl,2,4-difluorocyclopentyl, 2,5-difluorocyclopentyl,3,3-difluorocyclopentyl, 2,2,3-trifluorocyclopentyl,2,2,4-trifluorocyclopentyl, 2,2,5-trifluorocyclopentyl,2,3,3-trifluorocyclopentyl, 3,3,4-trifluorocyclopentyl,2,4,4-trifluorocyclopentyl, 2,2,3,3-tetrafluorocyclopentyl,2,2,4,4-tetrafluorocyclopentyl, 2,2,5,5-tetrafluorocyclopentyl,3,3,4,4-tetrafluorocyclopentyl, 2,2,3,4-tetrafluorocyclopentyl,2,2,3,5-tetrafluorocyclopentyl, 2,2,4,5-tetrafluorocyclopentyl,2,3,3,4-tetrafluorocyclopentyl, 2,3,3,5-tetrafluorocyclopentyl,3,3,4,5-tetrafluorocyclopentyl, 2,3,4,5-tetrafluorocyclopentyl,2,2,3,3,4-pentafluorocyclopentyl, 2,2,3,3,5-pentafluorocyclopentyl,2,2,3,4,4-pentafluorocyclopentyl, 2,2,3,5,5-pentafluorocyclopentyl,2,2,3,4,5-pentafluorocyclopentyl, 2,3,3,4,4-pentafluorocyclopentyl,2,3,3,5,5-pentafluorocyclopentyl, 2,3,3,4,5-pentafluorocyclopentyl,2,2,3,3,4,4-hexafluorocyclopentyl, 2,2,3,3,5,5-hexafluorocyclopentyl,2,2,3,3,4,5-hexafluorocyclopentyl, 2,3,3,4,4,5-hexafluorocyclopentyl,2,3,3,4,4,5-hexafluorocyclopentyl, 2,2,3,4,4,5-hexafluorocyclopentyl,2,2,3,3,4,4,5-heptafluorocyclopentyl,2,2,3,3,4,5,5-heptafluorocyclopentyl, and octafluorocyclopentyl.

A more particular value for E is CZ wherein Z is selected from the moreparticular values defined below.

More particular values of Ar as phenyl substituted with 0-2substitutents include those values of phenyl substituted with 0-1substituent, including phenyl, 2-, 3- and 4-fluorophenyl, 2- and3-chlorophenyl, 2- and 3-cyanophenyl, 2- and 3-hydroxyphenyl, 2- and3-methoxyphenyl, and 2- and 3-methylphenyl.

More particular values of Ar as a six-membered heteroaryl ringcontaining 1-2 nitrogen atoms include 2, 3-, and 4-pyridyl, and 2- and4-pyrimidinyl.

More particular values of Ar as a five-membered heteroaryl ringcontaining from 1-2 heteroatoms include 3- and 4-isothiazolyl, 2- and4-oxazolyl, 2- and 4-thiazolyl, 2- and 3-furyl, and 2- and 3- thienyl.

More particular values of Z as (1-4C)alkyl include values of(1-2C)alkyl, including methyl and ethyl.

More particular values of Z as (1-4C)alkoxy include values of(1-2C)alkoxy, including methoxy and ethoxy.

More particular values of Z as phenylthio substituted with from 0-2substitutents include those values of phenylthio substituted with 0-1substituent, including phenylthio, 2-, 3- and 4-fluorophenylthio, 2-,3-, and 4-chlorophenylthio, 2-, 3- and 4-cyanophenylthio, 2-, 3- and4-hydroxyphenylthio, 2-, 3- and 4-methoxyphenylthio, and 2-, 3- and4-methylphenylthio.

More particular values of Z as phenylsulfinyl substituted with from 0-2substitutents include those values of phenylsulfinyl substituted with0-1 substituent, including phenylsulfinyl, 2-, 3- and4-fluorophenylsulfinyl, 2-, 3- and 4-chlorophenylsulfinyl, 2-, 3- and4-cyanophenylsulfinyl, 2-, 3- and 4-hydroxyphenylsulfinyl, 2-, 3- and4-methoxyphenylsulfinyl, and 2-, 3- and 4-methylphenylsulfinyl.

More particular values of Z as phenylsulfonyl substituted with from 0-2substitutents include those values of phenylsulfonyl substituted with0-1 substituent, including phenylsulfonyl, 2-, 3- and4-fluorophenylsulfonyl, 2-, 3-, and 4-chlorophenylsulfonyl, 2-, 3-, and4-cyanophenylsulfonyl, 2-, 3-, and 4-hydroxyphenylsulfonyl, 2-, 3-, and4-methoxyphenylsulfonyl, and 2-, 3-, and 4-methylphenylsulfonyl.

More particular values of R2 and R3 as (1-3C)alkyl substituted by from 0to 2k+l groups selected from chloro and fluoro include those substitutedwith fluoro groups only, including fluoromethyl, difluoromethyl,trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl,1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl,1,2,2,2-tetrafluoroethyl, and 1,1,2,2,2-pentafluoroethyl.

A particular amide has formula Id wherein:

X and Z are selected from the group consisting of:

(A) X is ArY wherein

Y is a linking group selected from carbonyl, sulfinyl, and sulfonyl andAr is selected from the group consisting of phenyl, 2-, 3- and4-fluorophenyl, 2- and 3-chlorophenyl, 2- and 3-cyanophenyl, 2- and3-hydroxyphenyl, 2- and 3-methoxyphenyl, 2- and and 3-methylphenyl, 2,3-, and 4-pyridyl, 2- and 4-pyrimidinyl, 3- and 4-isothiazolyl, 2- and4-oxazolyl, 2- and 4-thiazolyl, 2- and 3-furyl, and 2- and 3-thienyl;

Z is selected from hydrogen, cyano, halo, hydroxy, (1-2C)alkyl, and(1-2C)alkoxy;

(B) X is CN, Z is phenylsulfonyl;

R² and R³ are independently selected from the group consisting of(1-3C)alkyl substituted by from 0 to 2k+l fluoro groups wherein k is thenumber of carbon atoms in the said (1-3C)alkyl, provided that R² and R³are not both methyl; and pharmaceutically acceptable in vivohydrolyzable esters of said amide; and pharmaceutically acceptable saltsof said amides and said esters.

A preferred amide has formula Id wherein X is ArY, and wherein:

Ar, Y, and Z are selected from the group consisting of:

(i) Y is sulfonyl, Z is hydrogen, and Ar is selected from the groupconsisting of:

phenyl substituted with 0-1 substituents, selected from phenyl, 2-, 3-,and 4-fluorophenyl, 2- and 3-chlorophenyl, 2- and 3-methoxyphenyl, 2-and 3-cyanophenyl, 2- and 3-hydroxyphenyl, and 2- and 3-methylphenyl;

six-membered heteroaryl rings selected from 2-, 3- and 4-pyridyl, and2-pyrimidinyl;

five-membered heteroaryl rings selected from 2-thienyl and 2-thiazolyl;

(ii) Y is sulfonyl, Ar is phenyl or 4-pyridyl, and Z is selected fromthe group consisting of cyano, fluoro, hydroxy, methoxy and methyl; and

(iii) Y is carbonyl, Z is hydrogen, and Ar is selected from the groupconsisting of phenyl and 2-pyridyl; and

R2 and R3 are independently selected from the group consisting of

(i) R² is trifluoromethyl and R³ is selected from methyl, ethyl, andTrifluoromethyl; and

(ii) R² is difluoromethyl and R³ is difluoromethyl; and thepharmaceutically acceptable in Vivo hydrolyzable esters of said amide,and pharmaceutically acceptable salts of said amide and saidhydrolyzable esters.

Where applicable, the S-configuration generally represents a preferredsterochemistry for compounds according to the invention.

Specifically preferred amides include the following:

N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propanamide;

S-(-)-N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;

N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;

S-(-)-N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;

N-[4-(4-Pyridylsulfonyl)phenyl]-3,3-difluoro-2-hydroxy-2-difluoro-methylpropanamide;

N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoro-methylpropanamide;

N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoro-methylpropanamide;and

N-[3-Hydroxy-4-(4-pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

The above compounds are preferred because they are selective for thebladder without significant effect on the cardiovascular system, asmeasured by blood pressure effects, in the in vivo test predictive ofselectivity which is described herein.

Amides of formula I can be made by processes which include processesknown in the chemical arts for the production of structurally analogouscompounds. Such processes for the manufacture of an amide of formula Ias defined above are provided as further features of the invention andare illustrated by the following procedures in which the meanings ofgeneric radicals are as given above unless otherwise qualified. Such aprocess can be effected, generally,

(a) by coupling an aniline of formula II with an acid of formula IIIwherein G is a hydroxy group. The reaction can be conducted in asuitable solvent and in the presence of a suitable coupling reagent.Suitable coupling reagents generally known in the art as standardpeptide coupling reagents can be employed, for example thionyl chloride,(see Morris et. al., J. Med. Chem., 34, 447, (1991)),carbonyldiimidazole (CDI) and dicyclohexylcarbodiimide, optionally inthe presence of a catalyst such as dimethylaminopyridine (DMAP) or4-pyrrolidinopyridine. Suitable solvents include dimethylacetamide,dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. Thecoupling reaction can be conducted in a temperature range of about -40°to 40° C.;

(b) by deprotecting a protected amide having formula IV wherein "PG" isa suitable protecting group such as a benzyl group; Examples of suitablereactants for use in cleaving the ether moiety to yield a hydroxyl groupinclude (1) hydrogen in the presence of palladium-on-carbon catalyst,i.e. hydrogenolysis; (2) hydrogen bromide or iodide; (3) trimethylsilyliodide; and (4) alkyl sulfides or phosphides. The reaction can beconducted in a suitable solvent such as ethanol, methanol, acetonitrile,or dimethylsulfoxide and at a temperature in the range of about -40° to100° C.

(c) in a compound of formula I wherein X is substituted or unsubstitutedphenylsulfinyl or phenylsulfonyl, by oxidizing a correspondingsubstituted or unsubstituted phenylsulfide. Suitable oxidizing agentsinclude potassium permanganate, oxone, sodium periodate, and hydrogenperoxide. The reaction can be conducted in a suitable solvent such asdiethyl ether, methanol, ethanol, water, acetic acid, and mixtures oftwo or more of the aforementioned. The reaction can be conducted at atemperature of -40° to 70° C.

(d) by reacting an amide of formula V with a base sufficiently basic(e.g., a lithium dialkylamide such as lithium diisopropyl amide) toyield an amide dianion, followed by reacting the dianion therebyproduced with oxygen in the presence of a reducing agent (e.g., such astriphenyl phosphine) to yield the corresponding compound of formula I;The sequence of reactions can be conducted at a temperature in the rangeof about -100° to 20° C. in a suitable solvent such as tetrahydrofuranor diethyl ether.

(e) in a compound of-formula Id wherein X is substituted orunsubstituted phenylsulfonyl, by reacting a corresponding substituted orunsubstituted compound of formula VI, wherein the value corresponding toX is substituted or unsubstituted phenylsulfonyl and Hal indicates ahalogen substituent (e.g., the corresponding chloride), with acorresponding alkali metal amide dianion having formula VII wherein Amis an alkali metal such as sodium or lithium; The reaction can beconducted at a temperature in the range of about -40° to about 100° C.and in a suitable solvent such as dimethylformamide, dimethylsulfoxide,or tetrahydrofuran.

(f) by reacting an (alkyl ester) compound of formula VIII, wherein R⁴ isa (1-4C)alkyl group (e.g. methyl, ethyl, or propyl) with a (2-3C)alkylmagnesium halide (i.e., a Grignard reagent); The reaction, a Grignardaddition to an ester, can be conducted at a temperature of about -100°to about 20° C. in a suitable solvent such as tetrahydrofuran or diethylether. Higher alkyl esters can be employed, but they provide nosynthetic advantage.

(g) when X is substituted or unsubstituted benzoyl (in formula I), byreacting a corresponding compound of formula IXa with a correspondingsubstituted or unsubstituted triphenylaluminum or tetraphenyltin andcarbon monoxide in the presence of a suitable catalyst such asbis-(triphenylphosphine)palladium (II) chloride; The reaction may beconducted at a temperature of from about -20° to about 100° C. in asuitable solvent such as benzene, toluene, tetrahydrofuran, or diethylether.

(h) when X is substituted or unsubstituted benzoyl, by oxidizing acompound of formula IXb to the corresponding compound of formula Iwherein X is the corresponding substituted or unsubstituted benzoylmoiety; Oxidizing agents such as bromine and pyridinium dichromate andsolvents such as, respectively, methanol and dichloromethane can besuitably employed.

If not commercially available, the necessary starting materials for theprocedures such as that described above may be made by procedures whichare selected from standard organic chemical techniques, techniques whichare analogous to the synthesis of known, structurally similar compounds,or techniques which are analogous to the above described procedure orthe procedures described in the examples. In the discussion whichfollows, "Ar" refers to an unsubstituted or substituted phenyl group ora heterocyclic radical, as previously defined.

In general, compounds of formulae IV, V, VIII, IXa, and IXb can be madein a manner analogous to that described in procedure (a) above formaking an amide of formula I; that is, by coupling an appropriatecorresponding aniline with an appropriate corresponding acid. Thus, tomake a protected amide of formula IV, a corresponding aniline of formulaII can be coupled with an acid of formula III wherein the groupcorresponding to G is OPG. The protected acid can be made by aconventional procedure, for example by (i) esterifying an acid offormula III wherein G is hydroxy by means of a conventionalesterification procedure such as reaction with a lower alcohol (e.g.,methanol) in the presence of an acid catalyst (for example sulfuricacid); (ii) reaction of the ester thus formed with an agent whichprovides the protecting group PG, such as benzyl chloride (to provide abenzyl protecting group) or any of the conventional silylating agentsknown and used for such purpose (such as 2-trimethylsilylethoxymethylchloride, SEM, in the presence of a suitable base such as sodiumhydroxide or triethylamine optionally in the presence of a catalyst suchas DMAP); and (iii) cleavage of the ester group under mild alkalineconditions (i.e., employing a base such as potassium carbonate) to yieldthe desired protected acid.

As a further example, a compound of formula IXa can be made by couplingan acid of formula III wherein G is hydroxy with an aniline of formulaII wherein the group corresponding to X is iodo and E is CH. It will beappreciated by those skilled in the art that compounds having the otherformulae noted above can be prepared in an analogous manner usingappropriate corresponding starting materials.

An aniline of formula XI wherein n=0, 1, or 2 (i.e., an aniline offormula II wherein X is ArS, ArSO, or ArSO₂) can be made by reducing thecorresponding nitro compound of formula XII with a suitable reducingagent as generally known in the art, see A. Courtin, Helv, Chim,. Acta,66, 1046 (1983); and H. Gilman et. al., J. Amer. Chem. Soc., 69, 2053,(1947). Suitable reducing agents include stannous chloride dihydrate inethanol conducted at a temperature of 20° to reflux, iron inwater-ethanol conducted at a temperature of 20° to reflux, and catalytichydrogenation using palladium or platinum catalyst conducted at atemperature of 20° to 50° C.

An aniline of formula XI wherein n=2 can also be made by the acidhydrolysis (aqueous HCl/ethanol at reflux) of an acetanilide of formulaXIII to afford the corresponding aniline.

A nitro compound of formula XII wherein n=1 or 2 can be made byoxidizing the corresponding compound of formula XII wherein n=0 (i.e.the corresponding sulfide), thereby yielding the corresponding compoundof formula XII wherein n-1 or 2, as desired. Suitable reagents for thepreparation of n=1 are sodium periodate in a suitable solvent such asmethanol or dioxane conducted at a temperature of 20° to 80° ; bromineand potassium carbonate in methylene chloride/water conducted at roomtemperature; and 30% hydrogen peroxide in acetic acid conducted at roomtemperature. Suitable reagents for the preparation of n=2 are potassiumpermanganate in acetic acid/water conducted at room temperature; 30%hydrogen peroxide in acetic acid conducted at 70° ; oxone inmethanol/water conducted at room temperature; and m-chloroperbenzoicacid in methylene chloride conducted at a temperature of 0° to reflux.

A nitro compound of formula XII wherein n=0 or 2 can also be made byreacting a corresponding alkali metal acid salt of formula ArSO_(n) Am,wherein Am is an alkali metal such as sodium, lithium, or potassium,with a halide of formula XIV wherein Hal indicates a halo substituent(such as chloro). The reaction is conducted in solvents such asethanol/water, dimethylformamide or dimethylacetamide at a temperatureof 20° to 155°.

A nitro compound of formula XII, wherein n=0 or 2, can also be made byreacting a corresponding compound of formula ArHal wherein Hal ishalogen (for example 2-chloro-5-nitropyridine) with a corresponding saltof formula XV (n=0 or 2) wherein Am is an alkali metal such as sodium,lithium or potassium. The reaction is conducted in solvents such asethanol/water, dimethylformamide or dimethylacetamide at a temperatureof 20° to 155°.

An aniline of formula XVI can be made by reacting a corresponding acidof formula ArCO₂ H or a corresponding anhydride of formula ArCO--O--COArwith aniline in the presence of polyphosphonic acid. See, for example,B,. Staskum, J. Org. Chem., 29, 2856, (1964) and A. Denton et. al., J.Chem. Soc., 4741, (1963).

It is noted that many of the starting materials for synthetic methods asdescribed above are commercially available and/or widely reported in thescientific literature.

In cases where compounds of formula I (or Id) are sufficiently basic oracidic to form stable acid or basic salts, administration of thecompound as a salt may be appropriate, and pharmaceutically acceptablesalts can be made by conventional methods such as those describedfollowing. Examples of suitable pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form aphysiologically acceptable anion, for example, tosylate,methanesulfonate, acetate, tartrate, citrate, succinate, benzoate,ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganicsalts may also be formed such as sulfate, nitrate, and hydrochloride.Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound of formula I (or its ester) with a suitable acidaffording a physiologically acceptable anion. It is also possible withmost compounds of the invention to make a corresponding alkali metal(e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g.,calcium) salt by treating an amide of formula I (and in some cases theester) with one equivalent of an alkali metal or alkaline earth metalhydroxide or alkoxide (e.g. the ethoxide or methoxide in aqueous mediumfollowed by conventional purification techniques.

In vivo hydrolyzable esters of compounds of the invention can be made bycoupling with a pharmaceutically acceptable carboxylic acid or anactivated derivative thereof. For example, the coupling can be carriedout by treating a parent amide of formula I with an appropriate acidchloride (for example, acetyl chloride, propionyl chloride, or benzoylchloride) or acid anhydride (for example, acetic anhydride, propionicanhydride, or benzoic anhydride) in the presence of a suitable base suchas triethylamine. Those skilled in the art will appreciate that othersuitable carboxylic acids (including their activated derivatives) forthe formation of in vivo hydrolyzable esters are known to the art andthese are also intended to be included within the scope of theinvention. Catalysts such as 4-dimethylaminopyridine can also beusefully employed.

When used to treat urinary incontinence, a compound of formula I isgenerally administered as an appropriate pharmaceutical compositionwhich comprises a compound of formula I as defined hereinbefore togetherwith a pharmaceutically acceptable diluent or carrier, the compositionbeing adapted for the particular route of administration chosen. Suchcompositions are provided as a further feature of the invention. Theymay be obtained employing conventional procedures and excipients andbinders and may be in a variety of dosage forms. For example, they maybe in the form of tablets, capsules, solutions or suspensions for oraladministration; in the form of suppositories for rectal administration;in the form of sterile solutions or suspensions for administration byintravenous, intravesicular (i.e., directly into the bladder),subcutaneous or intramuscular injection or infusion; or in the form of apatch for transdermal administration.

The dose of compound of formula I which is administered will necessarilybe varied according to principles well known in the art taking accountof the route of administration, the severity of the incontinencecondition, and the size and age of the patient. In general, a compoundof formula I will be administered to a warm blooded animal (such as man)so that an effective oral dose is received, generally a daily dose inthe range of about 50 to about 500 mg. For the specific compoundspreviously noted as being preferred because they are bladder selective,an effective oral dose can range from a total daily dose of 50 mg up toa dose of about 2000 mg. No untoward effects have been observed inlaboratory animals following administration of compounds according tothe invention at several multiples of the minimum effective dose in theanimal tests described hereinafter.

It will be apparent to those skilled in the art that a compound offormula I can be co-administered with other therapeutic or prophylacticagents and/or medicaments that are not medically incompatible therewith.

The actions of compounds of formula I as smooth muscle relaxants usefulas therapeutic agents for the treatment of urinary incontinence can beshown using suitably designed in vitro tests, such as the one describedfollowing. Compounds according to the invention typically exhibit anIC₅₀ on the order of 30 micromolar or less in the test. "IC50" is a yellunderstood term and means the concentration of test compound whichcauses a 50% decrease in the in vitro contraction of the bladder tissuedescribed in the following test.

Male albino Hartley guinea pigs (450-500 g) are sacrificed by cervicaldislocation. The lower abdominal cavity is opened and the urinarybladder located. Once located, it is cleaned of surrounding connectiveand adipose tissue. The two pelvic nerves on the ventral surface of thebladder are cut away, then the bladder body is removed above theentrance of the ureters. The bladder is washed in Krebs-Henseleit buffersolution (composition (mM): NaCl 118.0, KCl 4.7, MgSO₄ 1.2, KH₂ PO₄ 1.2,CaCl₂ 2.5, NaHCO₃ 25 and D-Glucose 11.1) and then placed on abuffer-soaked gauze in a petri dish. The dome of the bladder is cut offand discarded.

A mid-ventral longitudinal cut is made with scissors and the bladderlaid flat on the gauze. Strips are cut from the dome edge and the baseedge and discarded. The remaining detrusor mid-section is cut into twolatitudinal (horizontal) strips, with an approximate width of 2.0 mm.These two strips are cut in half at the mid-dorsal section, creatingfour strips of similar dimensions. Each strip thus contains both dorsaland ventral portions of the bladder.

Each individual strip is tied at one end directly to a glass support rodand a length of 4-0 black braided silk suture is tied to the other end.The glass rods are secured in 20 ml tissue baths and the length ofsuture attached to a force-displacement transducer (Grass model FT03).

The tissues are bathed in Krebs-Henseleit buffer solution. The bathingsolution is warmed to 37° C. and gassed with 5% CO₂ and 95% O₂, withvigorous bubbling. The solution should have a pH value close to 7.4.

The transducers are connected to a polygraph (Grass model 7E) andinterfaced with a Modular Instrument Micro 5000 signal processing systemand Biowindow Data Acquisition Software (run on Microsoft OS/2 with anIBM-compatible PC)

The polygraph is calibrated at 5 mV/cm and calibration checked forlinearity with weights of 5 and 0.5 grams.

The tissue is incubated in the buffer for 15 minutes without preloadtension, then 30 minutes with tension applied. The preload tensionapplied is 2 grams that relaxes to approximately 1 gram. The tissue iswashed at 15 minute intervals, with tension adjusted to 2 grams justprior to washing. After this 45 minute equilibration period, a primingdose of 15 mM KCl (total concentration in bath) is applied. The tissueis washed after 10 minutes and washed twice more at 15 minute intervalswith tension adjusted to 2 grams before each washing.

When the tissue relaxes to a steady state after the final washing, 15 mMKCl is again dosed. Once the tissue reaches a steady state the base linedata are acquired on the Biowindows Data Acquisition System. This isdone by averaging 5 minutes of data, sampling at 32 Hz. Once thebaseline is acquired, the experimental compounds are dosed in acumulative manner in half log unit increments. The contact time for eachdose is 10 minutes with the final 5 minutes being the period of timethat the dose response data are acquired. If 30 μM of the test compounddoes not abolish detrusor mechanical activity, then 30 μM cromakalim isdosed to establish a maximum response. The effects of the compounds areexpressed as % of maximum relaxation of agonist induced tension.

Typical IC₅₀ values in the above test are 1.27±0.31 μM for the compoundof Example 1 and 5.14±1.89 μM for the compound of Example 2.

It will be further appreciated by those skilled in the art that theefficacy of compounds according to the invention can be demonstrated bystandard assays in vivo. The following is a description of such astandard test which is used to evaluate smooth muscle relaxingcapability of test compounds.

Male Wistar rats weighing 450-550 grams are anesthetized with 20 mg/kg,intraperitoneal (i.p.) Nembutal and 80 mg/kg, i.p. Ketamine. The tracheais cannulated to prevent airway obstruction. Body temperature ismaintained by means of a heating pad. Arterial blood pressure and heartrate are measured with a pressure transducer connected to a polyethylenetube (PE 50) which has been inserted into the right carotid artery. Theright jugular vein is cannulated for drug administration. The urinarybladder is exposed through a midline abdominal incision and emptied ofurine by application of slight manual pressure. A catheter (PE 50) isinserted through the apex of the bladder dome around 3-4 mm into itslumen and tied with suture (4-0 silk) to prevent leakage. The bladdercatheter is connected to a pressure transducer for the measurement ofbladder pressure. The bladder is then placed back into the abdominalcavity and the incision is stitched closed except where the catheterexits the cavity. The bladder is allowed to equilibrate forapproximately 15 minutes. After the equilibration period, the rats areinfused with saline directly into the bladder at a rate of 0.05 ml/minfor the entire time of the experiment. The bladder pressure is thenmonitored for the start of bladder contractions. When the contractionsstart, the animal is then allowed to stabilize its pattern ofcontractions around 30 to 45 minutes before drug administration.

The test compounds are given intravenous and the cutoff dose is 3 mg/kg.The reference drug cromakalim (Smithkline-Beecham) has been evaluated inthis model and administered intravenous over the dose range of 0.05 to0.5 mg/kg.

The above in vivo assay enables an assessment of both the blood pressureand cystometric activity of test compounds. Blood pressure is measuredimmediately after drug injection and at 5, 15 and 30 minutes later.Micturition contractions are induced by a slow continuous infusion ofsaline directly into the bladder. The average change (in seconds fromcontrol) in the duration of the intercontraction interval (the timebetween contractions) over an approximate 20-min period is reported foreach compound.

Typical results are indicated for the Examples noted in Table 1 whichfollows:

                  TABLE 1                                                         ______________________________________                                                  CHANGE IN MBP                                                                                5    15   30   CHANGE                                CMPD    DOSE    Immed.   min  min  min  IN IC                                 ______________________________________                                        Example 5                                                                             3       -63      -52  -37  -28  +77                                   ______________________________________                                         Dose is mg/kg.                                                                MBP = mean arterial blood pressure. The values are mmHg and reflect           changes from control. The times shown are the immediate (Immed.) effect       and the effects at 5, 15, and 30 minutes after i.v. compound                  administration.                                                               IC = intercontraction interval. Change in IC = peak response in seconds       from control.                                                            

The following is a description of a test in vivo which is complimentaryto the above described tests and which can be used to ascertain if atest compound is active and, additionally, if the test compound exhibitsselectivity for-the bladder without significant cardiovascular effectswhen dosed orally. The specifically preferred compounds noted previouslyare active and selective in this test.

Male Wistar rats (400-500 g) were anesthetized with 50 mg/kg Nembutal,i.p. For each rat, the abdominal region and the front and back of theneck were shaved and povidone-iodine was applied to the skin. Forcarotid catheterization, the left carotid artery was exposed via a smallventral cervical incision. The exposed area was flushed with a 2%lidocaine HCl solution to relax the vessel. The catheter, filled with0.9% saline, was introduced approximately 2.4 cm into the artery so thatits tip resided in the aortic arch. The distal end of the catheter wasexteriorized at the nape of the neck, filled with heparin (1000units/ml) and heat sealed. For bladder catheterization, the catheterswere implanted according to the method of Yaksh TL, Durant PAC, BrentCR. Micturition in rats: A chronic model for study of bladder functionand effect of anesthesia. Am. J. Physiol. 251 (Regulatory IntegrativeComp. Physiol. 20): R1177-R1185, 1986. The bladder was exposed through amidline abdominal incision. A trocar was passed through the abdominalmuscle about 1 cm from the upper end of the incision and then tunneledsubcutaneously to emerge through the skin at the back of the neck. Asaline-filled catheter was passed through the trocar. A small opening inthe bladder dome was created with an Accu-Temp cautery. The catheter wasplaced into the bladder and secured with a 4-0 silk ligature. Thecatheter was flushed with saline and patency was noted. The external endof the catheter was heat-sealed to prevent urine leakage. The abdominalmuscles and the skin were sutured. Both catheters were threaded througha stainless steel anchor button (Instech), which was then sutured to thesubcutaneous muscle at the point of exteriorization. The skin wassutured closed over the button. The animals were allowed to recover fromanesthesia.

24-48 hours after surgery, each rat was placed in a metabolism cage andconnected via the anchor button to an Instech spring tether and swivelsystem to protect the catheters from damage and to allow the animal freemovement in the cage. The carotid catheter was connected to a GouldP23XL pressure transducer for blood pressure measurement. The bladdercatheter was connected to a pump for saline infusion and to a pressuretransducer by means of PE50 tubing and a 4-way stopcock. A toploadingbalance with a collection cup was placed under the cage for urine outputmeasurement.

The rats were weighed, orally sham-dosed (dosing needle introduced, butno fluid expelled), and transvesical saline infusion (0.18 ml/min) wasbegun and continued throughout the experiment. Variations in bloodpressure, heart rate, intravesical pressure and urine output wererecorded on either a Grass Polygraph or a Gould TA4000 recording system.The animals were allowed to equilibrate until the micturition patternbecame consistent (approx. 45-90 min.). At this point, a basal level ofeach experimental parameter was recorded and the rats were administeredby oral garage the appropriate dose of compound (in a 75% PEG400--saline vehicle) in concentrations such that the volume was 1 ml/kgbody weight. The effects of the compounds on experimental parameterswere followed for five hours after administration. Cromakalim(Smithkline-Beecham) was used as the reference standard.

Experimental results for both the interval between contractions and alsoheart rates were expressed as the mean ±S.E.M. % change from basallevel, with each animal serving as its own control. MAP is expressed asmean ±S.E.M mm Hg change from basal level. Typical values are listed inTable 2 for the Examples noted.

                  TABLE 2                                                         ______________________________________                                                Dose                    CMBP.sup.4                                    Compound                                                                              (mg/kg).sup.1                                                                          Time.sup.2                                                                            CIC.sup.3                                                                            (mm Hg) % CHR.sup.5                           ______________________________________                                        cromakalim                                                                            1.0      1       54 ± 5                                                                            -18 ± 4                                                                             20 ± 5                                             2        76 ± 15                                                                          -18 ± 6                                                                             15 ± 4                                             3       104 ± 5                                                                           -14 ± 5                                                                             13 ± 2                                             4       129 ± 5                                                                           -11 ± 4                                                                             10 ± 4                                             5       114 ± 25                                                                          -12 ± 3                                                                             9 ± 4                             example 61                                                                            3 mg/kg  1       35 ± 3                                                                             1 ± 1                                                                             -3 ± 2                                              2       53 ± 5                                                                            -1 ± 1                                                                             -4 ± 3                                              3       65 ± 5                                                                            -2 ± 1                                                                             -2 ± 4                                              4       57 ± 5                                                                            -1 ± 2                                                                             -2 ± 3                                              5        90 ± 10                                                                          -4 ± 1                                                                             -2 ± 2                             example 59                                                                            3 mg/kg  1       39 ± 5                                                                             0 ± 2                                                                              1 ± 1                                              2        74 ± 11                                                                           1 ± 2                                                                              2 ± 3                                              3       96 ± 9                                                                            -1 ± 1                                                                              0 ± 4                                              4       108 ± 6                                                                           -2 ± 1                                                                              2 ± 2                                              5       124 ± 9                                                                           -7 ± 1                                                                              3 ± 4                             ______________________________________                                         .sup.1 mg/kg is milligrams per kilogram of body weight.                       .sup.2 Time is measured in hours following (post) dosage.                     .sup.3 CIC is an acronym for change in intercontraction interval of the       bladder.                                                                      .sup.4 CMBP is an acronym for change in the mean arterial blood pressure.     .sup.5 % CHR is an acronym for percentage of change in heart rate.            Note: All values are relative to controls.                               

Compounds according to the invention are active in one or more of theabove-described tests. With reference to those (preferred) compoundspreviously listed as exhibiting selectivity for the bladder, mostcompounds from that list have also been tested in vivo in a dog model,and all which were tested exhibited activity and selectivity.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (C); operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18°-25°;

(ii) evaporation of solvent was carried out using a rotary evaporatorunder reduced pressure (600-4000 pascals; 4.5-30 mm Hg) with a bathtemperature of up to 60°;

(iii) flash chromatography was carried out on Merck Kieselgel (Art 9385)and column chromatography on Merck Kieselgel 60 (Art 7734); [thesematerials were obtained from E. Merck, Darmstadt, W. Germany]; thinlayer chromatography (TLC) was carried out on Analtech 0.25 mm silicagel GHLF plates (Art 21521), obtainable from Analtech, Newark, Del.,USA;

(iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;

(v) melting points are uncorrected and (d) indicates decomposition; themelting points given are those obtained for the materials prepared asdescribed; polymorphism may result in isolation of materials withdifferent melting points in some preparations;

(vi) all final products were essentially pure by TLC and hadsatisfactory nuclear magnetic resonance (NMR) spectra andmicroanalytical data;

(vii) yields are given for illustration only;

(viii) reduced pressures are given as absolute pressures in pascals(Pa); other pressures are given as gauge pressures in bars;

(ix) chemical symbols have their usual meanings; the folio ringabbreviations have also been used: v (volume), v (weight); mp (meltingpoint), L [liter(s)], mL (milliliters), mmol (millimoles), g [gram(s)],mg [milligram(s)], min (minutes), h (hour); and

(x) solvent ratios are given in volume:volume (v/v) terms.

EXAMPLE 1N-[4-(2-Fluorophenylsulfonyl)phenyl]-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methyl propanoic acid (1.42 g 9.0 mmol) inN,N-dimethylacetamide (13 mL) was rapidly added thionyl chloride (1.13g, 9.5 mmol) and the mixture (a precipitate formed after a few minutes)stirred at -15° to -5° C. for 1 hour.4-(2-Fluorophenylsulfonyl)benzenamine (1.51 g, 6.0 mmol) was then addedin one portion and the mixture allowed to stir at room temperatureovernight. The solution was poured into water, the cloudy solutiondecanted from the resulting gum and filtered through a thin pad ofCelite. The Celite pad was washed with methylene chloride and thesolution added to a solution of the gum in methylene chloride. Thecombined methylene chloride solution was dried (MgSO₄), filtered and thesolvent removed in vacuo. The resulting Mum was treated with hexane (100mL) and enough methylene chloride (ca. 100 mL) to yield a solution.Methylene chloride was then boiled off on a steam bath at atmosphericpressure until cloudiness developed. The solution was cooled andscratched with a spatula until crystal growth began, returned to thesteam bath and concentrated with swirling until the final volume was 100mL. After cooling the solid was filtered to yield the title propanamide(1.92 g, 82%) as a light tan solid; mp 124°-133° C. ¹ H-NMR (400 MHz, d₆-DMSO): 1.59 (s, 3H, CH₃), 7.41 (t, 1H, aromatic), 7.51 (t, 1H,aromatic), 7.59 (s, 1H, OH), 7.77 (m, 1H, aromatic), 7.85 (d, 2H, J=8.7Hz, aromatic), 7.98-8.06 (m, 3H, aromatic), 10.48 (s, 1H, NH). MS (CI,CH₄): 392(M+1).

Analysis for C₁₆ H₁₃ F₄ NO₄ S: Calculated: C, 49.11; M, 3.35; N, 3.58Found: C, 49.28; M, 3.51; N, 3.66

The starting 4- (2-fluorophenylsulfonyl)benzenamine is described in N.Sharghi and I. Lalezari, J. Chem. Eng. Data, 8, 276-8 (1963).

EXAMPLE 2N-[4-(2-Methylphenylsulfonyl)phenyl]-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-15° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methyl propanoic acid (1.42 g, 9.0 mmol) inN,N-dimethylacetamide (13 mL) was rapidly added thionyl chloride (1.13g, 9.5 mmol) and the mixture (a precipitate formed after a few minutes)stirred at -20° C. to -10° C. for 1 hour.4-(2-Methylphenylsulfonyl)benzenamine (1.48 g, 6.0 mmol) was then addedin one portion, washed in with 2 mL of N,N-dimethylacetamide and themixture allowed to stir at room temperature overnight. The solution waspoured into water, the cloudy solution decanted from the resulting gumand filtered through a thin pad of Celite. The Celite pad was washedwith methylene chloride and the solution added to a solution of the gumin methylene chloride. The combined methylene chloride solution wasdried (MgSO₄), filtered and the solvent removed in vacuo. The resultinggum was dissolved in a few mL of methanol and added dropwise to 100 mLof rapidly stirred 3N HCl. The aqueous phase was decanted from the gum,the gum dissolved in methylene chloride, dried (MgSO₄), filtered and thesolvent removed in vacuo. The residue was dissolved in 125 mL ofmethylene chloride and heated on a steam bath as 100 mL of hexane wasslowly added to replace the methylene chloride. When a volume of 125 mLwas reached more hexane (ca. 50 mL) was added to the cloud point. Aftercooling overnight the resulting solid was filtered to yield impureproduct. This material was further stirred with 300 mL of 0.5N HCl for45 min., the aqueous phase decanted off and the residual gum dissolvedin methylene chloride, dried (MgSO₄), filtered and the solvent removedin vacuo. The material was dissolved in 100 mL of methylene chloride, 50mL of hexane added and the solution heated on a steam bath to a finalvolume of 100 mL. After cooling the resulting solid was filtered anddried at 100°-120° C./0.1 torr. for 2.5 hours to yield the titlepropanamide (1.78 g, 77%) as a light tan solid; mp 126°-128° C. ¹ H-NMR(300 MHz, d₆ -DMSO): 1.58 (s, 3H, CH₃), 2.39 (s, 3H, aryl CH₃),7.37-8.10 (m, 8H, aromatic), 7.6 (broad s, 1H, OH), 10.4 (broad s, 1H,NH). MS (CI, CH₄): 388(M+1).

Analysis for C₁₇ H₁₆ F₃ NO₄ S: Calculated: C, 52.71; H, 4.16; N, 3.62Found: C, 52.64; H, 4.16; N, 3.59 882

The starting 4-(2-Methylphenylsulfonyl)benzenamine is described in H.Gilman and H. Smith Broadbent, J. Amer. Chem. Soc., 69, 2053 (1947).

EXAMPLE 3N-[4-(2-Methoxyphenylsulfonyl)phenyl]-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-15° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.42 g 9.0 mmol) inN,N-dimethylacetamide (13 mL) was rapidly added thionyl chloride (1.13g, 9.5 mmol) and the mixture (a precipitate formed after a few minutes)stirred at -15° C. to -5° C. for 1 hour.4-(2-Methoxyphenylsulfonyl)benzenamine (1.58 g, 6.0 mmol) was then addedin one portion and the mixture allowed to stir at room temperatureovernight. The solution was poured into 300 mL of 0.5N HCl, the clearsupernatent decanted off and the residual gum taken up in methylenechloride, dried (MgSO₄), filtered and the solvent removed in vacuo. Theresidue was dissolved in 100 mL of methylene chloride, filtered, treatedwith 50 mL of hexane and heated briefly on a steam bath until crystalsstarted to form. The final volume was taken to 200 mL with hexane, themixture refrigerated for 3 hours, and the crystals filtered and washedwith hexane. The solid was dissolved in 700 mL of refluxing methylenechloride and methylene chloride boiled off as 250 ml of hexane wasslowly added. The mixture was concentrated to a final volume of 375 mL.After cooling the solid was filtered and dried at 135°-140° C./0.1 torr.for 40 hours to yield the title propanamide. 0.1CH₂ Cl₂ (1.41 g, 57%) asa white solid; mp 209°-211° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.55 (s, 3H,CH₃), 3.72 (s, 3H, CH₃ O), 5.73 (s, 0.2H, CH₂ Cl₂), 7.11-7.17 (m, 2H,aromatic), 7.53 (s, 1H, OH), 7.61-7.97 (m, 6H, aromatic), 10.36 (s, 1H,NH). MS (CI, CH₄): 404(M+1).

Analysis for C₁₇ H₁₆ F₃ NO₅ S0.1CH₂ Cl₂ : Calculated: C, 49.87; H, 3.96;N, 3.40 Found: C, 49.71; H, 3.96; N, 3.35

The starting 4-(2-methoxyphenylsulfonyl)benzenamine was obtained asfollows:

a. 4-(2-Methoxyphenylsulfonyl)benzenamine.

To a stirred slurry of 2-methoxyphenyl-4-nitrophenyl sulfone (12.36 g,4.2 mmol) and 90 mL of absolute ethanol was added stannous chloridedihydrate (47.4 g, 21 mmol) in one portion. The mixture was heated to50° C. where an exothermic reaction caused the solution to stronglyreflux. The mixture was allowed to stir at ambient temperature for 30min., poured onto ice-water and made strongly basic by the addition of350 mL of 15% NaOH. The mixture was extracted with methylene chloride(3×275 mL), the extracts dried (MgSO₄), filtered, and the solventremoved in vacuo to yield a white solid which was recrystallized fromethyl acetate--hexane. After cooling the solid was filtered to yield thetitle benzenamine (5.38 g, 49%) as a white solid; mp 206°-208° C. ¹H-NMR (300 MHz, d₆ -DMSO): 3.75 (s, 3H, OCH₃), 6.10 (s, 2H, NH₂),6.56-6.61 (m, 2H, aromatic), 7.07-7.13 (m, 2H, aromatic),.7.49-7.61 (m,3H, aromatic), 7.90 (dd, 1H, J=8.1 & 1.7 Hz, aromatic). MS (CI, CH₄):264 (M+1).

Analysis for C₁₃ H₁₃ NO₃ S: Calculated: C, 59.30; H, 4.98; N, 5.32Found: C, 59.28; H, 5.04; N, 5.20

b. 2-Methoxyphenyl-4-nitrophenyl sulfone.

To a stirred solution of 2-methoxyphenyl-4-nitrophenyl sulfide (13.73 g,5.25 mmol) and acetic acid (800 mL) was rapidly added a solution ofpotassium permanganate (9.97 g, 6.3 mmol) in water (350 mL). Afterstirring for 45 min. the mixture was poured into water (2 L), clarifiedby the addition of sodium sulfite and the solid filtered, dried severalhours at 40° C. / 0.1 torr. and recrystallized three times from absoluteethanol (300 mL). The yield of title sulfone was 12.46 g, 81%; whiteplates, mp 140°-142° C. ¹ H-NMR (300 MHz, CDCl₃): 3.79 (s, 3H, OCH₃),6.94 (d, 1H, J=8.4 Hz, aromatic), 7.16 (t, J=7.6 1H, Hz aromatic),7.58-7.64 (m, 1H, aromatic), 8.13-8.19 (m, 3H, aromatic), 8.31-8.35 (m,2H, aromatic). MS (CI, CH₄): 294 (M+1).

Analysis for C₁₃ H₁₁ NO₅ S: Calculated: C, 53.24; H, 3.78; N, 4.78Found: C, 53.23; H, 3.79; N, 4.79

c. 2-Methoxyphenyl-4-nitrophenyl sulfide.

A solution of 4-chloronitrobenzene (11.23 g, 7.13 mmol) inN,N-dimethylformamide (75 mL) was added to 2-methoxythiophenol potassiumsalt [prepared by adding 2-methoxythiophenol (10.0 g, 7.13 mmol) to asolution of potassium hydroxide (4.00 g, 7.13 mmol) in methanol followedby removal of the methanol in vacuo] and washed in with an additional 15ml of N,N-dimethylformamide. After stirring at room temperatureovernight the mixture was poured into ice-water, stirred for 1 hour,filtered, the collected solid washed with water and dried overnight at40° C./0.1 torr. The pale yellow solid was recrystallized from 85%ethanol (150 mL), and then from hexane (700 mL) to yield the titlesulfide (13.8 g, 74%) as pale yellow needles, mp 90°-92° C. ¹ H-NMR (300MHz, CDCl3): 3.82 (s, 3H, OCH₃), 7.01-7.06 (m, 2H, aromatic), 7.10-7.15(m, 2H, aromatic), 7.45-7.55 (m, 2H, aromatic), 8.02-8.07 (m, 2H,aromatic). MS (CI, CH₄): 262(M+1).

Analysis for C₁₃ H₁₁ NO₃ S: Calculated: C, 59.76; H, 4.24; N, 5.36Found: C, 59.95; H, 4.25; N, 4.73

EXAMPLE 4N-(4-Phenylsulfonyl-3-cyanophenyl)-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 1.91 g (5.2 mmol) ofN-(4-phenyl-thio-3-cyanophenyl)-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamideand 150 mL of glacial acetic acid was added a solution of 0.99 g (6.3mmol) of potassium permanganate and 100 mL of water in one portion. Themixture was stirred at ambient temperature for 45 minutes, poured into400 mL of water, clarified with a little solid sodium bisulfite andextracted with three 250 mL portions of chloroform. The extracts dried(MgSO₄), filtered and the solvent removed to yield an oil which waschromatographed on 300 g of silica gel using a ethyl ether (0%, 10%, 15%and 20%) in methylene chloride gradient. The material was furtherrecrystallized from hexane containing a small amount of ethyl acetate toyield 1.57 g (75%) of the title propanamide as a white solid; mp163°-165° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.59 (s, 3H, CH₃), 7.66-7.77(m, 4H, aromatic, OH), 7.99 (d, 2H, J=7.3 Hz, aromatic), 8.32 (d, 1H,J=8.6 Hz, aromatic), 8.40-8.43 (m, 2H, aromatic), 10.77 (s, 1H, NH). MS(CI, CH₄): 399(M+1).

Analysis for C₁₇ H₁₃ F₃ N₂ O₄ S: Calculated: C, 51.26; H, 3.29; N, 7.03Found: C, 51.28; H, 3.31; N, 7.01

The startingN-(4-phenylthio-3-cyanophenyl)-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamidewas obtained as follows:

a.N-(4-Phenylthio-3-cyanophenyl)-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (2.16 g 13.7 mmol) inN,N-dimethylacetamide (20 mL) was rapidly added thionyl chloride (1.73g, 14.5 mmol) and the mixture (a precipitate formed after a few minutes)stirred at -20° C. to -10° C. for 1 hour. (4-Amino-2-cyanophenyl)phenylsulfide (2.08 g, 9.2 mmol) was then added in one portion and the mixtureallowed to stir at room temperature overnight. The solution was pouredinto 500 mL of water and extracted with two 100 mL portions of ethylether. The oil obtained in removal of the ethyl ether waschromatographed on 325 g of silica gel using an ethyl ether (0%, 5%, 10%and 20%) in methylene chloride gradient. The proper fractions werecombined, the solvent removed in vacuo and the residue heated overnightat 60° C./0.1 mm to yield 5.35 g (93%) ofN-(4-phenylthio-3-cyanophenyl)-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide,mp 124°-126° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.59 (s, 3H, CH₃),7.32-7.47 (m, 6H, aromatic), 7.59 (s, 1H, OH), 8.07 (dd 1H, J=8.8, 2.3Hz, aromatic), 8.33 (d, 1H, J=2.3 Hz, aromatic), 10.48 (s, 1H, NH). MS(CI, CH₄): 367(M+1).

b. 4-Amino-2-cyanophenyl phenyl sulfide.

To a stirred slurry of 4-nitro-2-cyanophenyl phenyl sulfide (13.3 g,5.19 mmol) and 100 mL of absolute ethanol was added stannous chloridedihydrate (58.6 g, 26 mmol) in one portion. The mixture was heated to60° C. where an exothermic reaction caused the solution to stronglyreflux. The mixture was allowed to stir at ambient temperature for 30min., poured onto ice-water and made strongly basic by the addition of350 mL of 15% NaOH. The mixture was extracted with methylene chloride(4×275 mL), the extracts dried (MgSO₄), filtered, and the solventremoved in vacuo to yield an oil which was chromatographed on 300 g ofsilica gel using a methylene chloride (20%, 40%, 60% 80% and 100%) inhexane gradient. The proper fractions were combined and the solventremoved to yield the 4-amino-2-cyano-phenyl phenyl sulfide (10.62 g,91%) as a pale yellow solid; mp 73°-75° C. ¹ H-NMR (300 MHz, CDCl₃):4.01 (s, 2H, NH₂), 6.78 (dd 1H, J=8.5, 2.6, aromatic), 6.95 (d, 1H,J=2.6, aromatic), 7.18-7.29 (m, 5H, aromatic), 7.34 (d, 1H, J=8.5,aromatic). MS (CI, CH₄): 227(M+1).

Analysis for C₁₃ H₁₀ N₂ S: Calculated: C, 69.00; H, 4.45; N, 12.38Found: C, 68.99; H, 4.59; N, 12.27

c. 4-Nitro-2-cyanophenyl phenyl sulfide.

4-Chloro-3-cyanonitrobenzene (12.5 g, 6.84 mmol) was added portionwiseto a stirred N,N-dimethylformamide (50 mL) solution of thiophenolpotassium salt [prepared by adding thiophenol (7.1 mL, 6.9 mmol) to asolution of potassium hydroxide (3.84 g, 6.84 mmol) in methanol followedby removal of the methanol in vacuo]. After stirring at 105° C. for 2.5hours the mixture was poured into ice-water, filtered, the collectedsolid washed with water, dissolved in 300 mL of refluxing ethanol(charcoal), filtered, treated with 35 mL of water and refrigerated. Theresulting pale yellow solid weighed 13.3 g (76%), mp 82°-84° C. ¹ H-NMR(250 MHz, CDCl₃): 6.93 (d, 1H, J=9.0 Hz, aromatic), 7.51-7.62 (m, 5H,aromatic), 8.12(dd, 1H, J=9.2, 2.5 Hz, aromatic), 8.46 (d, 1H, J=2.5 Hz,aromatic). MS (CI, CH₄): 257(M+1).

Analysis for C₁₃ H₈ N₂ O₂ S: Calculated: C, 60.93; H, 3.15; N, 10.93Found: C, 60.87; H, 3.41; N, 10.95

EXAMPLE 5N-[4-(Phenylsulfonyl)phenyl]-3,3,3,-trifluoro-2-hydroxy-2-methyl-propanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (3.96 g 25 mmol) inN,N-dimethylacetamide (36 mL) was rapidly added thionyl chloride (3.10g, 26 mmol) and the mixture (a precipitate formed after a few minutes)stirred at -15° C. to -5° C. for 1 hour. 4-(Phenylsulfonyl)benzenamine(3.97 g, 17 mmol) was then added in one portion and the mixture allowedto stir at room temperature overnight. The solution was poured intowater, the resulting solid was filtered off, washed with 3N HCl , thenwater and dried at 65° C. for 2 hours. The solid was dissolved in 300 mLof refluxing methylene chloride and stirred and heated as hexane wasadded to replace the methylene chloride as it boiled off. When 250 mL ofhexane had been added (precipitate formed at about 180 mL addition) themixture was concentrated to 250 mL and refrigerated. The yield of lighttan solid was 5.92 g (93%), mp 164°-166° C. ¹ H-NMR (250 MHz, d₆ -DMSO):1.59 (s, 3H, CH₃), 7.57-7.72 (m, 4H, OH, aromatic), 7.92-8.04 (m, 6H,aromatic), 10.43 (s, 1H, NH).

Analysis for C₁₆ H₁₄ F₃ NO₄ S: Calculated: C, 51.47; H, 3.78; N, 3.75Found: C, 51.22; H, 3.83; N, 3.72

EXAMPLE 6N-[4-(4-pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (4.28 g, 30.5 mmol) inN,N-dimethyl-acetamide (30 mL) was added thionyl chloride (3.63 g, 30.5mmol) and the mixture stirred at -10° to -15° C. for one hour.4-(4-Pyridylsulfonyl)benzenamine (4.77 g, 20.4 mmol) was added in oneportion and the mixture stirred at room temperature overnight. Thesolution was poured into water, the yellow solid filtered and purifiedby flash chromatography (50% v/v ethyl acetate in methylene chloride).Evaporation of the eluent and trituration of the resulting solid withhot methylene chloride yielded the title propanamide (4.61 g, 60%) as anoff-white solid; mp 255°-257° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.71 (s,3H, CH₃ g), 7.71 (s, 1H, OH), 8.01 (d, 2H, J=4.5 Hz, aromatic), 8.12 (d,2H, J=7.1 Hz, aromatic), 8.19 (d, 2H, J=7.1 Hz, aromatic), 9.00 (d, 2H,J=4.5 Hz, aromatic), 10.61 (s, 1H, NH). MS (CI, CH₄): 375(M+1).

Analysis for C₁₅ H₁₃ F₃ N₂ O₄ S: Calculated: C, 48.12; H, 3.51; N, 7.48Found: C, 48.02; H, 3.59; N, 7.42

The starting 4-(4-pyridylsulfonyl)benzenamine is described in T.Takahashi, J Shibasaki and M. Uchibayashi, Pharm. Bull. (Japan), 2, 30(1954).

EXAMPLE 7N-[4-(2-Pyrimidinylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.01 g, 6.4 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.76 g, 6.4mmol) and the mixture stirred at -10° to -15° C. for one hour.4-(2-Pyrimidylsulfonyl)benzenamine (1.00 g, 4.2 mmol) was added in oneportion to the orange solution and the mixture stirred at roomtemperature overnight. The brown mixture was poured into water andextracted with ethyl acetate (2×50 mL). The combined organic portionswere washed with water, dried (MgSO₄), filtered, and the solventdistilled to yield a tan solid. Flash chromatography of the solid(eluted with 10% v/v ethyl acetate in methylene chloride) andevaporation of the eluent yielded the title propanamide (1.05 g, 66%) asa white solid; mp 187°-190° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.60 (s, 3H,CH₃), 7.59 (s, 1H, OH), 7.79 (t, 1H, J=4.9 Hz, aromatic), 7.96 (d, 2H,J=8.9 Hz, aromatic), 8.06 (d, 2H, J=8.9 Hz, aromatic), 9.02 (d, 2H,J=4.8 Hz, aromatic), 10.49 (s, 1H, NH). MS (CI, CH₄): 376 (M+1).

Analysis for C₁₄ H₁₂ F₃ N₃ O₄ S: Calculated: C, 44.80; H, 3.22; N, 11.20Found: C, 44.86; H, 3.36; N, 11.06

4-(2-Pyrimidylsulfonyl)benzenamine is described in G. H. Singhal, P. M.Thomas and I. C. Popoff, J. Heterocyclic Chem., 5(3), 411 (1968).

EXAMPLE 8N-[5-(2-Phenylsulfonylpyridyl)]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution ofN-[5-(2-phenylthiopyridyl)]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide(1.50 g, 4.4 mmol) in glacial acetic acid (125 mL) was added a solutionof potassium permanganate (0.83 g, 5.3 mmol) in distilled water (85 mL).The dark brown mixture was stirred at room temperature for 45 min, thentreated with solid sodium sulfite until decolorized. The mixture wasdiluted with water and extracted with chloroform (3×250 mL). Thecombined organic portions dried (MgSO₄), filtered and the solventdistilled to yield the title propanamide as a white solid; mp 175°-177°C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.59 (s, 3H, CH₃), 7.65 (m, 4H, OH,aromatic), 7.95 (d, 2H, J=7.5 Hz, aromatic), 8.22 (d, 1H, J=8.7 Hz,aromatic), 8.54 (dd, 1H, J=8.7 and 2.4 Hz, aromatic), 9.00 (d, 1H, J=2.3Hz, aromatic), 10.73 (s, 1H, NH). MS (CI, CH₄): 375(M+1).

Analysis for C₁₅ H₁₃ F₃ N₂ O₄ S: Calculated: C, 48.12; H, 3.51; N, 7.48Found: C, 47.96; H, 3.62; N, 7.43

The startingN-[5-(2-phenylthiopyridyl)]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamidewas obtained as follows:

N-[5-(2-Phenylthiopyridyl)]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.59 g, 3.7 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.44 g, 3.7mmol) and the mixture stirred at -10° to -15° C. for one hour.5-Amino-2-phenylthiopyridine (0.50 g, 2.5 mmol) was added in one portionto the orange solution and the mixture stirred at room temperatureovernight. The brown mixture Was poured into water and the aqueoussolution extracted with ethyl acetate (2×50 mL). The combined organicportions were washed with water, dried (MgSO₄), filtered, and thesolvent distilled to yield a yellow oil. Flash chromatography of the oil(eluted with 10% v/v ethyl acetate in methylene chloride) andevaporation of the eluent yielded the title propanamide (0.59 g, 69%) asa white solid; mp 147°-150° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.57 (s, 3H,CH₃), 7.04 (d, 1H, J=8.7 Hz, aromatic), 7.47 (m, 6H, OH, aromatic), 8.05(dd, 1H, J=8.7 and 2.6 Hz, aromatic), 8.77 (d, 1H, J=2.4 Hz, aromatic),10.30 (s, 1H, NH). MS (CI, CH₄): 343(M+1).

Analysis for C₁₅ H₁₃ F₃ N₂ O₂ S: Calculated: C, 52.63; H, 3.83; N, 8.18Found: C, 52.25; H, 3.86; N, 8.13

5-Amino-2-phenylthiopyridine is described in H. C. Winter and F. E.Reinhart, J. Amer. Chem. Soc., 62, 3508 (1940).

EXAMPLE 9N-[4-(4-Fluorophenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.58 g, 10 mmol) inN,N-dimethylacetamide (15 mL) was added thionyl chloride (1.25 g, 10.5mmol) and the mixture stirred at -20° to -5° C. for 1 hour.4-Amino-4'-fluorobenzophenone (1.44 g, 6.7 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The reaction mixture was poured into water, the cloudy solution decantedfrom a gum and filtered through a thin pad of Celite. The Celite waswashed with methylene chloride and the solution added to a solution ofthe gum in methylene chloride. The combined methylene chloride solutionwas dried (MgSO₄), filtered and the solvent removed to yield an oil. Theoil was treated with 50 mL of hexane and enough methylene chloride todissolve the oil. The solution volume was reduced slightly on a steambath and the solution cooled and scratched until crystals formed. Thevolume was reduced further on the steam bath, the mixture refrigeratedfor several hours and the resulting solid filtered off. The 1.60 g ofimpure product was further purified by chromatography on 80 g of flashcolumn silica gel using ethyl ether as eluent. The solvent was strippedfrom the first 150 mL of eluent, the residual oil dissolved in 15 mL ofmethylene chloride and added to 250 mL of rapidly stirred hexane. Theresulting solid was collected and dried to yield the title propanamide(0.22 g, 58%) as a pale yellow solid; mp 131°-133° C. ¹ H-NMR (250 MHz,CDCl₃): 1.77 (s, 3H, CH₃), 4.09 (s, 1H, OH), 7.14-7.28 (m, 2H,aromatic),7.69-7.85 (m, 6H, aromatic), 8.68 (s, 1H, NH). MS (CI, CH₄): 356M+1).

Analysis for C₁₇ H₁₃ F₄ NO₃ : Calculated: C, 57.47; H, 3.69; N, 3.94Found: C, 57.30; H, 3.65; N, 3.90

The starting 4-amino-4'-fluorobenzophenone is described in B. Staskum,J. Org. Chem., 29, 2856 (1964).

EXAMPLE 10N-[4-[(3-Pyridylsulfonyl)phenyl]]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.76 g, 4.8 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.57 g, 4.8mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-(3-Pyridylsulfonyl)benzenamine (0.75 g, 3.2 mmol) was added in oneportion to the orange solution and the mixture stirred at roomtemperature overnight. The brown solution was poured into water andextracted with ethyl acetate (2×50 mL). The combined organics were dried(MgSO₄), filtered and the solvent distilled to yield a tan solid.Recrystallization from ethyl acetate/hexane yielded the titlepropanamide (0.89 g, 74%) as an off-white solid; mp 207°-209° C. ¹ H-NMR(300 MHz, d₆ -DMSO): 1.57 (s, 3H, CH₃), 7.58 (s, 1H, OH), 7.65 (dd, 1H,J=8.1, 4.9 Hz, aromatic), 8.02 (d, 4H, J=4.6 Hz, aromatic), 8.34 (dd,1H, J=8.3, 1.9 Hz, aromatic), 8.85 (dd, 1H, J=4.8, 1.6 Hz, aromatic),9.12 (d, 1H, J=2.2 Hz, aromatic), 10.61 (s, 1H, NH). MS (CI, CH₄):375(M+1).

Analysis for C₁₅ H₁₃ F₃ N₂ O₄ S: Calculated: C, 48.12; H, 3.51; N, 7.48Found: C, 48.11; H, 3.56; N, 7.40

The starting 4-(3-Pyridylsulfonyl)benzenamine was obtained as follows:

a. 4-(3-Pyridylsulfonyl)benzenamine.

A stirred solution of 4-nitrophenyl 3-pyridyl sulfone (1.60 g, 6.1 mmol)and stannous chloride dihydrate (6.83 g, 30.2 mmol) in absolute ethanol(20 mL) was heated at reflux for 45 min. The reaction mixture was pouredinto ice water, and the aqueous solution basified with sodiumbicarbonate (pH=8-9) and extracted with ethyl acetate (2×200 mL). Theorganics were combined, dried (MgSO₄), filtered, and the solventdistilled to yield the title benzenamine (1.10 g, 79%) as a pale yellowsolid; mp 182°-184° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 6.29 (broad s, 2H,NH₂), 6.64 (d, 2H, J=11.2 Hz, aromatic), 7.58 (m, 1H, aromatic), 7.61(d, 2H, J=11.1 Hz, aromatic), 8.21 (dd, 1H, J=9.8, 2.4 Hz, aromatic),8.78 (dd, 1H, J=9.9, 1.4 Hz, aromatic), 9.01 (d, 1H, J=2.4 Hz). MS (CI,CH₄): 235(M+1).

Analysis for C₁₁ H₁₀ N₂ O₂ S: Calculated: C, 56.40; H, 4.30; N, 11.96Found: C, 56.64; H, 4.54; N, 11.48

The starting 4-nitrophenyl 3-pyridyl sulfone is described in U.S. Pat.No. 2761866.

EXAMPLE 11N-[4-(2-Thienylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.50 g, 3.1 mmol) inN,N-dimethylacetamide (7 mL) was added thionyl chloride (0.37 g, 3.1mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-(2-Thienylsulfonyl)benzenamine (0.50 g, 2.1 mmol) was added in oneportion to the orange solution and the mixture stirred at roomtemperature overnight. The brown solution was poured into water and theaqueous solution extracted with ethyl acetate (2×50 mL). The organicswere combined, dried (MgSO₄), filtered and the solvent distilled toyield a tan solid. Flash chromatography of the solid (eluted with 5% v/vethyl acetate in methylene chloride) and evaporation of the eluentyielded the title propanamide (0.61 g, 77%) as an off-white solid; mp158°-161° C. ¹ H-NMR (250 MHz, d6-DMSO): 1.57 (s, 3H, CH₃), 7.21 (dd,1H, J=4.9, 4.0 Hz, aromatic), 7.56 (s, 1H, OH), 7.81 (dd, 1H, J=3.8, 1.5Hz, aromatic), 8.00 (m, 5H, aromatic) 10.43 (s, 1H, NH). MS (CI, CH₄):380(M+1).

Analysis for C₁₄ H₁₂ F₃ NO₄ S₂ : Calculated: C, 48.12; H, 3.51; N, 7.48Found: C, 48.11; H, 3.56; N, 7.40

4-(2-Thienylsulfonyl)benzenamine is described in H. Burton, and W. A.Davy, J. Chem. Soc. 527 (1948).

EXAMPLE 12N-[4-[(2-Pyridylsulfonyl)phenyl)]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.76 g, 4.8 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.57 g, 4.8mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-(2-Pyridylsulfonyl)benzenamine (0.75 g, 3.2 mmol) was added in oneportion to the orange solution and the mixture stirred at roomtemperature overnight. The brown solution was poured into water and theaqueous solution extracted with ethyl acetate (2×25 mL). The organicswere combined, dried (MgSO₄), filtered and the solvent distilled toyield a tan solid. Recrystallization from ethyl acetate/hexane yieldedthe title propanamide (0.95 g, 79%) as an off-white solid; mp 162°-163°C. ¹ H-NMR (250 MHz, d₆ -DMSO): 1.58 (s, 3H, CH₃), 7.59 (s, 1H, OH),7.67 (m, 1H, aromatic), 7.92 (d, 2H, J=8.9 Hz, aromatic), 8.02 (d, 2H,J=8.9 Hz, aromatic), 8.15 (m, 2H, aromatic), 8.67 (d, 1H, J=4.2 Hz,aromatic), 10.44 (s, 1H, NH). MS (CI, CH₄): 375(M+1).

Analysis for C₁₅ H₁₃ F₃ N₂ O₄ S: Calculated: C, 48.12; H, 3.51; N, 7.48Found: C, 48.31; H, 3.62; N, 7.36

The starting 4-(2-pyridylsulfonyl)benzamine is obtained as follows:

a. 4-(2-Pyridylsulfonyl)benzenamine.

A stirred solution of 4-nitrophenyl 2-pyridyl sulfone (6.50 g, 24.6mmol) and stannous chloride dihydrate (27.72 g, 123.0 mmol) in absoluteethanol (200 mL) was heated at reflux for 25 min. The reaction mixturewas poured into ice water, and the aqueous solution basified with sodiumbicarbonate (pH=8-9) and extracted with ethyl acetate (2×400 mL). Theorganics were combined, dried (MgSO₄), filtered, and the solventdistilled to yield the title benzenamine (5.12 g, 89%) as a white solid;mp 158°-160° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 6.27 (broad s, 2H, NH₂),6.66 (d, 2H, J=8.7 Hz, aromatic), 7.61 (m, 3H, aromatic), 8.08 (d, 2H,J=4.9 Hz, aromatic), 8.68 (d, 1H, J=4.9, aromatic). MS (CI, CH₄):235(M+1).

Analysis for C₁₁ H₁₀ N₂ O₂ S: Calculated: C, 56.40; H, 4.30; N, 11.96Found: C, 56.38; H, 4.43; N, 11.91

4-Nitrophenyl 2-pyridyl sulfone is described in G. C. Pappalardo and A.Scarlata, Farmaco Ed. Science, 33(12), 945 (1978).

EXAMPLE 13N-[(3-Chloro-(4-phenylsulfonyl)phenyl)]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.66 g, 4.2 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.50 g, 4.2mmol) and the mixture stirred at -10° to -15° C. for 1 hour.3-Chloro-4-phenyl-sulfonylbenzenamine (0.75 g, 2.8 mmol) was added inone portion to the orange solution and the mixture stirred at roomtemperature overnight. The brown solution was poured into water and theaqueous solution extracted with ethyl acetate (2×50 mL). The organicswere combined, washed with water, dried (MgSO₄), filtered and thesolvent distilled to yield a tan foam. Flash chromatography of the solid(eluted with 10% v/v ethyl acetate in methylene chloride) andevaporation of the eluent yielded the title propanamide (1.07 g, 94%) asan off-white solid; mp 141°-143° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 1.58(s, 3H, CH₃), 7.68 (m, 4H, aromatic, OH), 7.89 (d, 1H, J=6.5 Hz,aromatic), 8.11 (d, 2H, J=8.2 Hz, aromatic), 8.26 (d, 2H, J=8.4 Hz,aromatic), 10.60 (s, 1H, NH). MS (CI, CH₄): 408(M+1).

Analysis for C₁₆ H₁₃ ClF₃ NO₄ S: Calculated: C, 47.13; H, 3.22; N, 3.43Found: C, 46.72; H, 3.32; N, 3.34

The starting 3-chloro-4-phenylsulfonylbenzenamine is described in U.S.Pat. No. 3576872.

EXAMPLE 14N-[4-(2-Chlorophenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.89 g, 5.6 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.67 g, 5.6mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-(2-Chlorophenylsulfonyl)benzenamine (1.00 g, 3.7 mmol) was added inone portion to the orange solution and the mixture stirred at roomtemperature overnight. The brown solution was poured into water and theaqueous solution extracted with ethyl acetate (2×50 mL). The organicswere combined, washed with water, dried (MgSO₄), filtered and thesolvent distilled to yield a tan solid. Recrystallization from methylenechloride/hexane yielded the title propanamide (1.43 g, 94%) as anoff-white solid; mp 136°-138° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 1.58 (s,3H, CH₃), 7.57 (s, 1H, OH), 7.67 (m, 3H, aromatic), 7.88 (d, 2H, J=8.8Hz, aromatic), 8.02 (d, 2H, J=8.8 Hz, aromatic), 8.26 (d, 1H, J=6.6 Hz,aromatic), 10.46 (s, 1H, NH). MS (CI, CH₄): 408(M+1).

Analysis for C₁₆ H₁₃ C₁ F₃ NO₄ S: Calculated: C, 47.13; H, 3.22; N, 3.43Found: C, 46.93; H, 3.17; N, 3.40

4-(2-Chlorophenylsulfonyl)benzenamine is described in H. Gilman and H.Smith Broadbent, J. Amer. Chem. Soc, 69, 2053 (1947).

EXAMPLE 15N-(4-Cyano-3-phenylsulfonylphenyl)-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred solution of 1.50 g (4.1 mmol) ofN-(4-Cyano-3-phenylthiophenyl)-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide (1,50 g, 4.1 mmol) and 120 mL of glacial acetic acid wasadded a solution of potassium permanganate (0.78 g, 4.9 mmol) and 78 mLof water in one portion. The mixture was stirred at ambient temperaturefor 45 minutes, poured into 300 mL of water, clarified with a littlesolid sodium bisulfite and extracted with three 275 mL portions ofchloroform. The extracts were dried (MgSO₄), filtered and the solventremoved to yield a white solid which was recrystallized from ethylacetate/hexane to yield, after drying at 100° C./0.1 mm, 1.38 g (85%) ofthe title propanamide as a white solid; mp 185°-187° C. ¹ H-NMR (250MHz, d₆ -DMSO): 1.62 (s, 3H, CH₃), 7.67-7.79 (m, 4H, aromatic),7.97-8.01 (m, 2H, aromatic, OH), 8.07 (d, 1H, J=8.6 Hz, aromatic), 8.26(dd 1H, J=8.5, 2.0 Hz, aromatic), 8.90 (d, 1H, J=2.1 Hz), 10.90 (s, 1H,NH). MS (CI, CH₄): 399(M+1).

Analysis for C₁₇ H₁₃ F₃ N₂ O₄ S: Calculated: C, 51.26; H, 3.29; N, 7.03Found: C, 51.52; H, 3.28; N, 6.96

The startingN-(4-cyano-3-phenylthiophenyl)]-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamidewas prepared as follows:

a. N-(4-Cyano-3-phenylthiophenyl)-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.62 g 10.2 mmol) inN,N-dimethylacetamide (15 mL) was rapidly added thionyl chloride (1.30g, 10.9 mmol) and the mixture (a precipitate formed after a few minutes)stirred at -20° C. to -5° C. for 1 hour. 4-Cyano-3-phenylthiobenzenamine(1.55 g, 6.85 mmol) was then added in one portion and the mixtureallowed to stir at room temperature overnight. The solution was pouredinto water, extracted with ethyl ether (2×100 mL); the etheral extractsdried (MgSO₄), filtered and the solvent removed in vacuo. The residuewas chromatographed on 315 g of silica gel using a ethyl ether (0%, 10%,and 20%) in methylene chloride gradient. The proper fractions werecombined, the solvent removed in vacuo and the residue dissolved in amixture of 100 mL hexane and 150 mL methylene chloride. Most of themethylene chloride was distilled off as the solution was scratched toinduce crystal growth. After cooling the solid was collected and driedat 85° C./0.1 mm to yield the title propanamide (2.38 g, 91%); mp111°-113° C. ¹ H-NMR (250 MHz, CDCl₃): 1.67 (s, 3H, CH₃), 3.68 (s, 1M,OH), 7.27 (d, 1H, J=1.9 Hz, aromatic), 7.40-7.51 (m, 5H, aromatic),7.59-7.69 (m, 2H, aromatic), 8.51 (s, 1H, NH). MS (CI, CH₄): 367(M+1).

Analysis for C₁₇ H₁₃ F₃ N₂ O₂ S: Calculated: C, 55.73; H, 3.58; N, 7.65Found: C, 55.27; H, 3.69; N, 7.51

b. 4-Cyano-3-phenylthiobenzenamine.

3-Chloro-4-cyanobenzenamine (20.0 g, 13.1 mmol) was added to aN,N-dimethylformamide (115 mL) solution of thiophenol potassium salt[prepared by adding thiophenol (13.5 mL, 13.1 mmol) to a solution ofpotassium hydroxide (7.35 g, 13.1 mmol) in methanol followed by removalof the methanol in vacuo]and washed in with an additional 15 ml ofN,N-dimethylformamide. After stirring at 140° C. for 16 hours themixture was poured into water, extracted with ethyl ether (3×150 mL) andthe solvent removed in vacuo to yield a red oil. The oil waschromatographed on silica gel using methylene chloride as eluent. Thefractions containing product (TLC- silica gel, 2% methanol/chloroform)were combined, the solvent removed and the material rechromatographedusing 2:1 methylene chloride/hexane as eluent. The proper fractions werecombined, concentrated to a low volume, treated with hexane and cooled(dry ice) and scratched as crystals formed. The white solid weighed 8.29g (30%); mp 69°-71° C. ¹ H-NMR (250 MHz, CDCl₃): 4.07 (s, 2H, NH₂), 6.29(d, 1H, J=2.2 Hz, aromatic), 6.46 (dd 1H, J=8.3, 2.2 Hz, aromatic),7.36-7.50 (m, 6H, aromatic). MS (CI, CH₄): 227(M+1).

Analysis for C₃ H₁₀ N₂ S: Calculated: C, 69.00; H, 4.45; N, 12.38 Found:C, 69.05; H, 4.59; N, 12.39

EXAMPLE 16N-[4-[(2-Thiazolylsulfonyl)phenyl]]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.12 g, 7.1 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.85 g, 7.1mmol) and the mixture stirred at -10° to -15° C. for 1 hour.2-[(4-Aminophenyl)sulfonyl]thiazole (1.14 g, 4.7 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The reaction mixture was poured into water and the resulting tan solidwas filtered and recrystallized from methylene chloride/hexane to yieldthe title propanamide (1.13 g, 63%) as a white solid; mp 161°-163° C. ¹H-NMR (300 MHz, d₆ -DMSO): 1.57 (s, 3H, CH₃), 7.58 (s, 1H, OH), 7.98 (d,2H, J=8 Hz, aromatic), 8.06 (d, 2H, J=8.8 Hz, aromatic), 8.08 (d, J=3.3Hz, aromatic), 8.25 (d, 1H, J=3.2 Hz, aromatic), 10.51 (s, 1H, NH). MS(CI, CH₄): 381(M+1).

Analysis for C₁₃ H₁₁ F₃ N₂ O₄ S₂ : Calculated: C, 41.04; H, 2.92; N,7.37 Found: C, 40.96; H, 2.93; N, 7.36

The starting 2-[(4-aminophenyl) sulfonyl]thiazole was obtained asfollows:

a. 2-[(4-Aminophenyl)sulfonyl]thiazole was

A stirred solution of 2-[(4-nitrophenyl)sulfonyl]thiazole (1.50 g, 5.6mmol) and stannous chloride dihydrate (6.26 g, 27.7 mmol) in absoluteethanol (25 mL) was heated at reflux for 1 hour. The reaction mixturewas poured into ice water, and the aqueous solution basified with 15%NaOH and extracted with ethyl acetate (2×200 mL). The combined organicportions were dried (MgSO₄), filtered, and the solvent removed to yielda solid which on trituration with diethyl ether and filtration yieldedthe title thiazole (1.21 g, 89%) as a pale yellow solid, mp 148°-150° C.¹ H-NMR (250 MHz, d₆ -DMSO): 6.44 (br s, 2H, NH₂), 6.66 (d, 2H, J=8.8Hz, aromatic), 7.61 (d, 2H, J=8.7 Hz, aromatic), 8.03 (d, 1H, J=3.2 Hz,aromatic), 8.14 (d, 1H, J=3.2 Hz, aromatic). MS (CI, CH₄): 241(M+1).

Analysis for C₉ H₈ N₂ O₂ S₂ ; 0.25 H₂ O: Calculated: C, 44.14; H, 3.30;N, 11.44 Found: C, 44.37; H, 3.35; N, 11.44

b. 2-[(4-Nitrophenyl)sulfonyl]thiazole.

To a stirred solution of 2-4-nitrophenylthio)thiazole (7.20 g, 30.2mmol) in glacial acetic acid (200 mL) was added a solution of potassiumpermanganate (5.73 g, 36.0 mmol) in distilled water (90 mL). The darkbrown mixture was stirred at room temperature for 2 hours, then treatedwith solid sodium sulfite to destroy excess permanganate. The mixturewas diluted with water and filtered to yield a tan solid.Recrystallization from absolute ethanol yielded the title thiazole(1.63M, 20%) as a cream colored solid; mp 159°-161° C. ¹ H-NMR (250 MHz,d₆ -DMSO): 6.66 (d, 2H, J=8.8 Hz, aromatic), 7.61 (d, 2H, J=8.7 Hz,aromatic), 8.03 (d, 1H, J=3.2 Hz, aromatic), 8.14 (d, 1H, J=3.2 Hz,aromatic). MS (CI, CH₄): 271(M+1).

Analysis for C₉ H₆ N₂ O₄ S₂ : Calculated: C, 40.00; H, 2.24; N, 10.37Found: C, 39.94; H, 2.27; N, 10.37

The starting 2-4-nitrophenylthiothiazole is described in M. Bosco, V.Liturri, L. Troisi, L. Foriani, and P. E. Todesco, J. Chem. Soc. PerkinTrans. II, 508 (1974).

EXAMPLE 17N-[4-[(5-Thiazolylsulfonyl)phenyl]]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.03 g, 6.5 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.77 g, 6.5mmol) and the mixture stirred at -10° to -15° C. for 1 hour.5-[(4-Aminophenyl)sulfonyl]thiazole (1.04 g, 4.3 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The reaction mixture was poured into water and filtered through a pad ofCelite. The Celite was washed with methylene chloride (2×50 mL) and thecombined organic portions were dried over MgSO₄, filtered, and thesolvent removed in vacuo to yield a tan solid. Recrystallization fromethyl acetate/hexane yielded the title propanamide (1.21 g, 74%) as awhite solid; mp 191°-193° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.58 (s, 3H,CH₃), 7.59 (s, 1H, OH), 7.99 (d, 2H, J=7.5 Hz, aromatic), 8.06 (d, 2H,J=7.5 Hz, aromatic), 8.57 (s, 1H, aromatic), 9.47 (s, 1H, aromatic),10.49 (s, 1H, NH). MS (CI, CH₄): 381(M+1).

Analysis for C₁₃ H₁₁ F₃ N₂ O₄ S₂ : Calculated: C, 41.05; H, 2.91; N,7.37 Found: C, 41.05; H, 2.93; N, 7.36

The starting 5- [(4-aminophenyl) sulfonyl I thiazole was obtained asfollows:

a. 5-[(4-Aminophenyl)sulfonyl]thiazole.

A stirred solution of 5-[(4-nitrophenyl)sulfonyl]thiazole (1.72 g, 6.4mmol) and stannous chloride dihydrate (7.17 g, 31.8 mmol) in absoluteethanol (25 mL) was heated at reflux for 1 hour. The reaction mixturewas poured into ice water, the aqueous solution basified with solidsodium bicarbonate and extracted with ethyl acetate (2×200 mL). Thecombined organic portions were dried (MgSO₄), filtered, and the solventremoved to yield an orange solid. Flash chromatography (eluted with 10%ethyl acetate in methylene chloride) and evaporation of the solventyielded the title thiazole (1.20 g, 78%) as a pale yellow solid; mp158°-160° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 6.35 (br s, 2H, NH₂), 6.65 (d,2H, J=8.9 Hz, aromatic), 7.61 (d, 2H, J=8.7 Hz, aromatic), 8.39 (s, 1H,aromatic), 9.38 (s, 1H, aromatic). MS (CI, CH₄): 241(M+1).

Analysis for C₉ H₈ N₂ O₂ S₂ : Calculated: C, 44.99; H, 3.36; N, 11.66Found: C, 44.94; H, 3.38; N, 11.68

b. 5-[(4-Nitrophenyl)sulfonyl]thiazole.

To a cooled (-5° C.), stirred solution of2-amino-5-[(4-nitrophenyl)sulfonyl]thiazole (5.15 g, 18.1 mmol) in 85%phosphoric acid (200 mL) was added dropwise a solution of sodium nitrite(1.56 g, 22.6 mmol) in distilled water (10 mL) at such a rate tomaintain the internal temperature between -5° and 5° C. When theaddition was complete the reaction mixture was stirred for 1 hour at 0°C. then treated dropwise with 50% hypophosphoric acid (15 mL). After theaddition, the ice bath was removed and reaction mixture stirred at roomtemperature for 3 hours during which time moderate frothing occurred.The brown solution was diluted with water (total volume=1 L),neutralized with 28% ammonium hydroxide and filtered. Flashchromatography of the resulting brown solid (eluted with 5% v/v ethylacetate in methylene chloride) yielded the title thiazole (1.72 g, 35%)as a yellow solid; mp 168°-170° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 8.32 (d,2H, J=12.6 Hz, aromatic), 8.45 (d, 2H, J=12.8 Hz, aromatic), 8.74 (s,1H, aromatic), 9.578 (s, 1H, aromatic). MS (CI, CH₄): 271(M+1).

Analysis for C₉ H₆ N₂ O₄ S₂ : Calculated: C, 39.40; H, 2.24; N, 10.36Found: C, 39.68; H, 2.33; N, 10.22

The starting 2-amino-5-[(4-nitrophenyl)sulfonyl]thiazole was purchasedcommercially.

EXAMPLE 18N-[4-(2-Pyrazinylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.01 g, 6.4 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.76 g, 6.4mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-Aminophenylsulfonylpyrazine (1.00 g, 4.2 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The reaction mixture was poured into water and the solid collected bysuction filtration. Flash chromatography (eluted with 20% v/v ethylacetate in methylene chloride) of the solid, evaporation of the eluent,and trituration with diethyl ether yielded the title propanamide (1.26g, 81%) as an off-white solid; mp 181°-183° C. ¹ H-NMR (250 MHz, d₆-DMSO): 1.58 (s, 3H, CH₃), 7.57 (s, 1H, OH), 7.98 (d, 2H, J=8.9 Hz,aromatic), 8.06 (d, 2H, J=9.0 Hz, aromatic), 8.81 (d, 1H, J=2.2 Hz,aromatic), 8.97 (d, 1H, J=2.2 Hz, aromatic), 9.39 (s, 1H, aromatic),10.48 (s, 1H, NH). MS (CI, CH₄): 376(M+1).

Analysis for C₁₄ H₁₂ F₃ N₃ O₄ S: Calculated: C, 44.80; H, 3.22; N, 11.20Found: C, 44.84; H, 3.29; N, 11.11

The starting 4-aminophenylsulfonylpyrazine was obtained as described:

a. 4-Aminophenylsulfonylpyrazine.

A stirred solution of 4-nitrophenylsulfonylpyrazine (2.50 g, 9.4 mmol)and stannous chloride dihydrate (10.62 g, 47.1 mmol) in absolute ethanol(30 mL) was heated at reflux for 1 hour. The reaction mixture was pouredinto ice water, and the aqueous solution basified with solid sodiumbicarbonate and extracted with ethyl acetate (2×200 mL). The combinedorganic portions were dried (MgSO₄), filtered, and the solvent distilledto yield an off-white solid. Recrystallization from absolute ethanolyielded the title pyrazine (1.90 g, 86%) as a white solid; mp 174°-177°C. ¹ H-NMR (300 MHz, d₆ -DMSO): 6.37 (br s, 2H, NH₂), 6.65 (d, 2H, J=8.6Hz, aromatic), 7.61 (d, 2H, J=8.6 Hz, aromatic), 8.78 (d, 1H, J=2.3 Hz,aromatic), 8.90 (d, 1H, J=2.2 Hz, aromatic), 9.27 (s, 1H, aromatic). MS(CI, CH₄): 236(M+1).

Analysis for C₁₀ H₉ N₃ O₂ S: Calculated: C, 51.05; H, 3.86; N, 17.86Found: C, 51.06; H, 3.94; N, 17.76

b. 4-Nitrophenylsulfonylpyrazine.

To a stirred solution of 4-nitrophenylthiopyrazine (3.00 g, 12.9 mmol)in glacial acetic acid (150 mL) was added potassium permanganate (2.44g, 15.4 mmol) in distilled water (90 mL). The dark brown mixture wasstirred at room temperature for 30 min, then treated with solid sodiumsulfite to destroy excess permanganate. The mixture was diluted withwater and filtered to yield the title pyrazine (2.68 g, 78%) as anoff-white solid; mp 159°-161° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 8.30 (d,2H, J=8.3 Hz, aromatic), 8.46 (d, 2H, J=8.4 Hz, aromatic), 8.85 (d, 1H,J=3.4 Hz, aromatic), 9.03 (d, 1H, J=3.4 Hz, aromatic), 9.40 (s, 1H,aromatic). MS (CI, CH₄): 266(M+1).

Analysis for C₁₀ H₇ N₃ O₄ S: Calculated: C, 45.28; H, 2.66; N, 15.84Found: C, 45.26; H, 2.64; N, 15.95

c. 4-Nitrophenylthiopyrazine.

A stirred solution of chloropyrazine (6.71 g, 58.6 mmol) and potassium4-nitrothiophenolate (12.45 g, 64.4 mmol) in dimethylformamide (40 mL)was heated at 110° C. for 4 hours. The reaction mixture was poured intoice water and the brown solid that precipitated was filtered.Recrystallization from absolute ethanol yielded the title pyrazine (4.30g, 30%) as a yellow solid; mp 88°-90° C. ¹ H-NMR (300 MHz, d₆ -DMSO):7.77 (d, 2H, J=6.7 Hz, aromatic), 8.24 (d, 2H, J=6.6 Hz, aromatic), 8.57(m, 2H, aromatic), 8.72 (d, 1H, J=1.2 Hz, aromatic). MS (CI, CH₄):234(M+1).

Analysis for C₁₀ H₇ N₃ O₂ S: Calculated: C, 51.50; H, 3.02; N, 18.02Found: C, 51.50; H, 3.00; N, 17.96

EXAMPLE 19N-[4-(2-Pyridylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.20 g, 7.6 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.90 g, 7.6mmol) and the mixture stirred at -10° to -15° C. for 1 hour.2-(4-Aminobenzoyl)pyridine (1.00 g, 5.0 mmol) was added in one portionand the reaction mixture stirred overnight at room temperature. Thereaction mixture was poured into water and the aqueous solutionextracted with ethyl acetate (2×50 mL). The combined organics were dried(MgSO₄), filtered and the solvent removed in vacuo to yield a brown oil.Flash chromatography (eluted with 5 % v/v ethyl acetate in methylenechloride) of the oil, evaporation of the eluent, and trituration withdiethyl ether yielded the title propanamide (1.07 g, 63%) as a whitesolid; mp 151°-154° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 1.58 (s, 3H, CH₃),7.58 (s, 1H, OH), 7.98 (d, 2H, J=8.9 Hz, aromatic), 8.06 (d, 2H, J=9.0Hz, aromatic), 8.81 (m, 2H, aromatic), 8.97 (d, 1H, J=2.2 Hz, aromatic),9.39 (s, 1H, aromatic), 10.48 (s, 1H, NH). MS (CI, CH₄): 339(M+1).

Analysis for C₁₆ H₁₃ F₃ N₂ O₃ : Calculated: C, 56.81; H, 3.87; N, 8.28Found: C, 56.50; H, 3.91; N, 8.21

The starting 2-(4-aminobenzoyl)pyridine is described in E. Koenigs, H.Menscing and P. Kirsh, Bet., 59B, 1717 (1926).

EXAMPLE 20N-[4-(3-Chlorophenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifiuoro-2-hydroxy-2-methylpropanoic acid (0.22 g, 1.4 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.17 g, 1.4mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-Amino-3'-chlorodiphenylsulfone (0.75 g, 2.8 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The reaction mixture was poured into water and the aqueous solutionfiltered through a pad of Celite. The Celite was extracted withmethylene chloride (200 mL) which was dried (MgSO₄), filtered and thesolvent removed to yield a tan solid. Flash chromatography of the solid(eluted with 5% v/v ethyl acetate in methylene chloride) and evaporationof the eluent yielded the title propanamide (0.22 g, 58%) as a whitesolid; mp 154°-156° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 1.58 (s, 3H, CH₃),7.57 (s, 1H, OH), 7.65 (t, 1H, J=8.0 Hz, aromatic), 7.77 (d, 1H, J=7.8Hz, aromatic), 7.91 (d, 1H, J=7.8 Hz, aromatic), 8.01 (m, 5H, aromatic),10.60 (s, 1H, NH). MS (CI, CH₄): 408(M+1).

Analysis for C₁₆ H₁₃ ClF₃ NO₄ S: Calculated: C, 47.13; H, 3.22; N, 3.43Found: C, 46.81; H, 3.37; N, 3.34

The starting 4-amino-3'-chlorodiphenylsulfone was purchasedcommercially.

EXAMPLE 21N-[4-[(3-Methylphenylsulfonyl)phenyl]]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.43 g, 2.7 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.32 g, 2.7mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-[(3-Methylphenyl)sulfonyl]benzenamine (0.45 g, 1.8 mmol) was added inone portion and the reaction mixture stirred at room temperatureovernight. The mixture was poured into water and the aqueous solutionfiltered through a pad of Celite. The Celite was washed with methylenechloride (100 mL) and the organic extract dried (MgSO₄), filtered andthe solvent removed in vacuo to yield a tan solid which was purified byflash column chromatography (10% v/v ethyl acetate/methylene chloride).Evaporation of the solvent from the proper fractions andrecrystallization of the resulting-solid from methylene chloride/hexaneyielded the title propanamide (0.52 g, 74%) as a white solid; mp164°-166° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.57 (s, 3H, CH₃), 2.38 (s,3H, aryl CH₃), 7.49 (dd, 2H, J=5.1, 1.0 Hz, aromatic), 7.56 (s, 1H, OH),7.73 (m, 2H, aromatic), 7.91 (d, 2H, J=8.9 Hz, aromatic), 8.00 (d, 2H,J=8.9 Hz, aromatic), 10.42 (s, 1H, NH). MS (CI, CH₄): 388(M+1).

Analysis for C₁₇ H₁₆ F₃ NO₄ S: Calculated: C, 52.71; H, 4.16; N, 3.62Found: C, 52.71; H, 4.28; N, 3.54

The starting 4-[(3-methylphenyl)sulfonyl]benzenamine was prepared in thefollowing manner:

a. 4-[(3-Methylphenyl)sulfonyl]benzenamine.

A stirred solution of 3-methylphenyl 4-nitrophenyl sulfone (0.50 g, 1.8mmol) and stannous chloride dihydrate (2.03 g, 9.0 mmol) in absoluteethanol (5 mL) was heated at reflux for 1 hour. The reaction mixture waspoured into ice water and the aqueous solution basified with 15% NaOHand extracted with ethyl acetate (2×100 mL). The combined organicextracts were dried (MgSO₄), filtered, and the solvent removed in vacuoto yield an off-white solid. Recrystallization from absoluteethanol/hexane yielded the title benzenamine (0.45 g, 100%) as a whitesolid; mp 183°-185° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 2.36 (s, 3H, CH₃),6.17 (s, 2H, NH₂), 6.61 (dd, 2H, J=7.0, 1.8 Hz, aromatic), 7.43 (d, 2H,J=7.1 Hz, aromatic), 7.54 (d, 2H, J=8.7 Hz, aromatic), 7.63 (m, 2H,aromatic). MS (CI, CH₄): 248(M+1).

Analysis for C₁₃ H₁₃ NO₂ S: Calculated: C, 63.14; H, 5.30; N, 5.66Found: C, 63.13; H, 5.28; N, 5.64

The starting 3-methylphenyl 4-nitrophenyl sulfone was purchasedcommercially.

EXAMPLE 22N-[(4-Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (10.54 g, 66 mmol) inN,N-dimethylacetamide (100 mL) was added thionyl chloride (7.94 g, 66mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-Aminobenzophenone (8.67 g, 44 mmol) was added in one portion and thereaction mixture stirred at room temperature overnight. The mixture waspoured into water and the white solid that precipitated upon stirringwas filtered from solution, dried on the filter for 1 hour, andrecrystallized from ethyl acetate/hexane (1:2 v/v). The first cropyielded the title propanamide (9.51 g, 64%) as a white solid; mp151°-153° C. A second crop was filtered upon cooling of the filtrate for72 hours to yield an additional 3.21 g (22%) of a white solid which wasidentical to the first crop by melting point and spectral properties. ¹H-NMR (300 MHz, d₆ -DMSO): 1.61 (s, 3H, CH₃), 7.54-7.59 (m, 3H, aromaticand OH), 7.65-7.71 (m, 3H, aromatic), 7.75 (d, 2H, J=8.5 Hz, aromatic),7.98 (d, 2H, J=8.5 Hz, aromatic), 10.35 (s, 1H, NH). MS (CI, CH₄):338(M+1).

Analysis for C₁₇ H₁₄ F₃ NO₃ : Calculated: C, 60.54; H, 4.23; N, 4.15Found: C, 60.33; H, 4.23; N, 4.12

The starting 4-aminobenzophenone was purchased commercially.

EXAMPLE 23N-[4-[(3-Pyridylcarbonyl)phenyl]]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.63 g, 4.0 mmol) inN,N-dimethylacetamide (7 mL) was added thionyl chloride (0.48 g, 4.0mmol) and the mixture stirred at -10° to -15° C. for 1 hour.3-(4-Aminobenzoyl)pyridine (0.66 g, 3.3 mmol) was added in one portionand the reaction mixture stirred at room temperature overnight. Themixture was poured into water and the aqueous solution extracted withethyl ether (2×100 mL). The combined organic extracts were dried(MgSO₄), filtered, and the solvent removed in vacuo to yield a paleyellow solid. Recrystallization from absolute ethanol/hexane yielded thetitle propanamide (0.42 g, 37%) as a white solid; mp 206°-208° C. ¹H-NMR (300 MHz, d₆ -DMSO): 1.60 (s, 3H, CH₃), 7.57 (s, 1H, OH),7.58-7.62 (m, 1H, aromatic), 7.79 (dd, 2H, J=7.0, 1.7 Hz, aromatic),7.98 (dd, 2H, J=7.0, 1.7 Hz, aromatic), 8.08-8.12 (m, 1H, aromatic),8.83 (dd, 1H, J=4.8, 1.7 Hz, aromatic), 8.87 (d, 1H, J=1.7 Hz,aromatic), 10.38 (s, 1H, NH). MS (CI, CH₄): 339(M+1).

Analysis for C₁₆ H₁₃ F₃ N₂ O₃ : Calculated: C, 56.81; H, 3.87; N, 8.28Found: C, 56.60; H, 3.88; N, 8.23

The starting 3-(4-aminobenzoyl)pyridine was obtained as follows:

a. 3-(4-Aminobenzoyl)pyridine.

A stirred solution of 3-(4-nitrobenzoyl)pyridine (1.08 g, 4.7 mmol) andstannous chloride dihydrate (5.34 g, 23.7 mmol) in absolute ethanol (50mL) was heated at reflux for 1 hour. The reaction mixture was pouredinto ice water and the aqueous solution basified with solid sodiumbicarbonate and extracted with ethyl acetate (2×150 mL). The combinedorganic extracts were dried (MgSO₄), filtered, and the solvent removedin vacuo to yield a yellow solid. Purification of the solid by flashchromatography (ethyl ether) and evaporation of the eluent yielded thetitle pyridine (0.71 g, 76%) as a yellow solid; mp 103°-105° C. ¹ H-NMR(300 MHz, d₆ -DMSO): 6.31 (s, 2H, NH₂), 6.64 (d, 2H, J=8.6 Hz,aromatic), 7.52°-7.58 (m, 3H, aromatic), 7.97°-8.01 (m, 1H, aromatic),8.74-8.77 (m, 2H, aromatic). MS (CI, CH₄): 199(M+1).

The starting 3-(4-nitrobenzoyl)pyridine is described in F. Bryans, andF. L. Pyman, J. Chem. Soc., 549 (1929).

EXAMPLE 24N-[4-(Phenylsulfonyl)phenyl]-1-hydroxy-cyclopropylcarboxamide.

A solution of 1-hydroxycyclopropanecaboxylic acid (0.66 g, 6.44 mmol) indry dimethylacetamide (10 ml) was stirred under a nitrogen atmosphere at-15° C. Thionyl chloride (0.77 g, 6.44 mmol) was added and the resultingmixture was allowed to stir at -15° C. for 1 hour.4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and thereaction mixture was stirred at -15° C. for a further 15 mins. Thesolution was then allowed to warm to room temperature where it wasstirred overnight. The reaction mixture was poured onto ice, extractedwith ethyl acetate, and the combined ethyl acetate portions were washedwith 1M HCl. After drying (MgSO₄) the ethyl acetate was removed byevaporation to give a buff-colored solid. Crystallization of thismaterial from ethyl acetate/hexane yielded the title tertiary carbinol,(0.82 g, 60%) as a white solid; mp=214.5°-216° C. ¹ H-NMR (250 MHz, d₆-DMSO): 0.98 (m, 2H, 2 CH₂), 1.15 (m, 2H, CH₂), 6.63 (s, 1H, OH), 7.65(m, 3H, ARM), 7.95 (m, 6H, ArH), 10.29 (s, 1H, NH). MS (CI, CH₄):318(M+1, 100).

Analysis for C₁₆ H₁₅ NO₄ S: Calculated: C, 60.55; H, 4.76; N, 4.41Found; C, 60.51; H, 4.77; N, 4.40

EXAMPLE 25 N-[4-(Phenylsulfonyl)phenyl]-2-hydroxy-2-ethylbutanamide.

A solution of 2-ethyl-2-hydroxybutyric acid (1.14 g, 8.69 mmol) in drydimethylacetamide was stirred under a nitrogen atmosphere at -15° C.Thionyl chloride (1.03 g, 8.69 mmol) was added and the resulting mixturewas allowed to stir at -15° C. for 1 hour. 4-Phenylsulfonylaniline (1.34g, 5.74 mmol) was then added and the reaction mixture was stirred at-15° C. for a further 15 mins. The solution was then allowed to warm toroom temperature where it was stirred for 48 hours. The reaction mixturewas poured onto ice, extracted with ethyl acetate, basified to pH 12 andextracted further with ether. The combined ether portions weredried-over MgSO₄ and evaporated to give a gold-colored oil.Crystallization of this material from Et20/hexane yielded an impuresolid. Flash chromatography of this material on silica gel eluting withmethylene chloride provided the title tertiary carbinol(0.16 g, 8%) as awhite solid; mp=116°-119° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 0.80 (t, 6H, 2CH3), 1.54 (m, 2H, CH2), 1.73 (m, 2H, CH2), 5.37 (s, 1H, OH), 7.64 (m,3H, ArH), 7.94(m, 6H, ArH), 9.89 (s, H, NH). MS (CI, CH₄): 348(M+1,100).

Analysis for C₁₈ H₂₁ NO₄ S. 0.25 H₂ O: Calculated: C, 61.43; H, 6.16; N,3.98 Found: C, 61.57; H, 6.02; N, 4.09

EXAMPLE 26 N-[4-(phenylsulfonyl)phenyl]-2-hydroxy-2-methylbutanamide.

A solution of 2-hydroxy-2-methyl butyric acid (0.76 g, 6.4 mmol) in drydimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at-10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resultingmixture was allowed to stir at -10° C. for 1 hour.4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and thereaction mixture was stirred at -10° C. for a further 15 mins. Thesolution was then allowed to warm to room temperature where it wasstirred overnight. The reaction mixture was poured onto water, extractedwith ethyl acetate, and the combined ethyl acetate portions were washedwith water, and brine. After drying (Na₂ SO₄) the ethyl acetate wasremoved by evaporation. Crystallization from ethyl acetate/hexaneyielded the title tertiary carbinol (0.89 g, 62.5%) as a colorlesscrystalline solid; mp=163.0°-165.0° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 0.82(t, J=7 Hz, 3H, CH₃), 1.32 (s, 3H, CH₃), 1.56 (m, J=7 Hz, 1H, CH₂), 1.76(m, J=7 Hz, 1H, CH₂), 5.65 (s, 1H, OH), 7.64 (m, 3H, ArH), 7.91 (m, 4H,ArH, 8.01 (d, J=11.1 Hz, 2H, ArH), 9.98 (s, 1H, NH). MS (CI, CH₄):334(M+1, 100).

Analysis for C₁₇ H₁₉ NO₄ S: Calculated: C, 61.24; H, 5.74; N, 4.20Found: C, 61.15; H, 5.60; N, 4.52

EXAMPLE 27 N-[4-(Phenylsulfonyl)phenyl]-1-hydroxy-cyclopentanecarboxamide.

A solution of 1-hydroxycyclopentanecarboxylic acid (0.76 g, 6.4 mmol) indry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at-10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resultingmixture was allowed to stir at -10° C. for 1 hour.4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and thereaction mixture was stirred at -10° C. for a further 15 mins. Thesolution was then allowed to warm to room temperature where it wasstirred overnight. The reaction mixture was poured onto water, extractedwith ethyl acetate, and the combined ethyl acetate portions were washedwith water, and brine. After drying (Na₂ SO₄) the ethyl acetate wasremoved by evaporation. Crystallization from ethyl acetate/hexaneyielded the title tertiary carbinol (0.70 g, 47%) as a white solid;mp=214.0°-216.0° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.73 (m, 6H, CH₂), 1.97(m, 2H, CH₂), 5.67 (s, 1H, OH), 7.64 (m, 3H, ArH), 7.94 (m, 6H, ArH),10.13 (s, 1H, NH). MS (CI, CH₄): 346(M+1, 100).

Analysis for C₁₈ H₁₉ NO₄ S: Calculated: C, 62.59; H, 5.54; N, 4.06Found: C, 62.67; H, 5.58; N, 4.00

EXAMPLE 28 N-[4-(Phenylsulfonyl)phenyl]-3-fluoro-2-hydroxy-2-methylpropanamide.

A solution of 2-hydroxy-2-fluoromethylpropionic acid (0.78 g, 6.4 mmol)in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphereat -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and theresulting mixture was allowed to stir at -10° C. for 1 hour.4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and thereaction mixture was stirred at -10° C. for a further 15 mins. Thesolution was then allowed to warm to room temperature where it wasstirred overnight. The reaction mixture was poured onto water, extractedwith ethyl acetate, and the combined ethyl acetate portions were washedwith water, and brine. After drying (Na₂ SO₄) the ethyl acetate wasremoved by evaporation to give an amber foam. Trituration withether/methylene chloride yielded the title tertiary carbinol (0.75 g,52%) as a light tan solid; mp=189°-192° C. ¹ H-NMR (300 MHz, d₆ -DMSO):1.31 (s, 3H, CH₃), 4.38 (dd, J=72 and 9.4 Hz, 1H, CH₂ F), 4.58 (dd, J=72and 9.3 Hz, 1H, CH₂ F), 6.29 (s, 1H, OH), 7.58-7.68 (m, 4H, ArH),7.89-8.02 (m, 5H, ArH), 10.16 (S, 1H, NH). MS (CI, CH₄): 338(M+1, 100).

Analysis for C₁₆ H₁₆ FNO₄ S . 0.1 H₂ O: Calculated: C, 56.66; H, 4.81;N, 4.13 Found: C, 56.40; H, 4.74; N, 4.02

EXAMPLE 29N-[4-(4-Pyridylsulfonyl)phenyl]-3-fluoro-2-hydroxy-2-methylpropanamide.

A solution of 2-hydroxy-2-fluoromethylpropionic acid (0.53 g, 4.33 mmol)in dry dimethylacetamide (12 ml) was stirred under a nitrogen atmosphereat -10° C. Thionyl chloride (0.52 g, 4.33 mmol) was added and theresulting mixture was allowed to stir at -10° C. for 1 hour.4-Phenylsulfonylaniline (0.68 g, 2.89 mmol) was then added and thereaction mixture was stirred at -10° C. for a further 15 mins. Thesolution was then allowed to warm to room temperature where it wasstirred overnight. The reaction mixture was poured onto water and the pHadjusted to pH 8.0 with sodium bicarbonate solution. The aqueoussolution was extracted with ethyl acetate, and the combined ethylacetate portions were washed with water, and brine. After drying (Na₂SO₄) the ethyl acetate was removed by evaporation to give ayellow-orange solid. The solid was washed with ether/methylene chlorideto yield the title tertiary carbinol (0.32 g, 32%) as a pale yellowsolid; mp=209°-211° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 1.31 (s, 3H, CH₃),4.38 (dd, J=72 and 9.4 Hz, 1H, CH₂ F), 4.58 (dd, J=72 and 9.3 Hz, 1H,CH₂ F), 6.31 (s, 1H, OH), 7.87 (d, J=6 Hz, 2H, PyH), 7.96 (d, J=8.9 Hz,2H, PhH), 8.06 (d, J=8.9 Hz, 2H, PhH), 8.86 (d, J=6 Hz, 2H, PyH), 10.22(s, 1H, NH). MS (CI, CH₄): 339(M+1, 100).

Analysis for C₁₅ H₁₅ FN₂ O₄ S: Calculated: C, 53.25; H, 4.47; N, 8.28Found: C, 52.85; H, 4.50; N, 8.05

EXAMPLE 30N-[4-(Phenylcarbonyl)phenyl]-3-fluoro-2-hydroxy-2-methylpropanamide.

A solution of 2-hydroxy-2-fluoromethylpropionic acid (0.93 g, 7.65 mmol)in dry dimethylacetamide (20 ml) was stirred under a nitrogen atmosphereat -10° C. Thionyl chloride (0.91 g, 7.65 mmol) was added and theresulting mixture was allowed to stir at -10° C. for 1 hour.4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and thereaction mixture was stirred at -10° C. for a further 15 mins. Thesolution was then allowed to warm to room temperature where it wasstirred overnight. The reaction mixture was poured onto water, extractedwith ethyl acetate, and the combined ethyl acetate portions were washedwith water, and brine. After drying (Na₂ SO₄) the ethyl acetate wasremoved by evaporation to give an straw-colored foam. Chromatography onsilica gel, eluting with ethyl acetate/hexane (1:1) gave the tertiarycarbinol (0.75 g, 48%) as a white powder; mp=146°-148° C. ¹ H-NMR (300MHz, d₆ -DMSO): 1.36 (s, 3H, CH₃), 4.38 (dd, J=72 and 9.4 Hz, 1H, CH₂F), 4.58 (dd, J=72 and 9.3 Hz, 1H, CH₂ F), 6.32 (s, 1H, OH), 7.56 (t,J=7.7 Hz, 2H, ArH), 7.65-7.76 (m, 5H, ArH), 7.9 (d, J=8.7 Hz, 2H, ArH),10.08 (s, 1H, NH). MS (CI, CH₄): 302(M+1, 100).

Analysis for C₁₇ H₁₆ FNO₃ : Calculated: C, 67.76; H, 5.35; N, 4.65Found: C, 67.45; H, 5.41; N, 4.58

EXAMPLE 31N-[4-(Phenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanamide.

A. solution of4'-phenylsulfonyl-2-benzyloxy-2,2-bis(trifluoromethyl)acetanilide (0.32g, 0.62 mmol) in absolute ethanol (120 ml) was hydrogenated using a 10%Palladium/carbon catalyst for 3.5 hours. The mixture was filteredthrough Celite and the filtrate evaporated to yield an oil whichcrystallized on standing to give the title tertiary carbinol (89%) as awhite solid; mp=94°-98° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 7.86 (m, 3H,ArH), 7.92 (m, 6H, ArH), 9.8 (brs, 1H, OH), MS (Fab(-ve ion)): 426(M-1,100%).

Analysis for C₁₆ H₁₁ F₆ NO₄ S: Calculated: C, 44.97; H, 2.60; N, 3.28Found: C, 44.60; H, 2.57; N, 3.14

a.N-[4-(Phenylsulfonyl)phenyl]-3,3,3-trifluoro-2-benzyloxy-2-trifluoromethyl-propanamide.

A solution of 2-benzyloxy-2,2-bis(trifluoromethyl)acetic acid (0.10 g,0.33 mmol) in dry benzene (3 ml) was stirred under a nitrogenatmosphere. Thionyl chloride (0.18 g, 1.52 mmol) was added followed bythree drops of dimethylformamide and the resulting solution was refluxedfor 20 minutes. After cooling the solution was evaporated to dryness invacuo. Benzene (10 ml) was added and the evaporation repeated to givethe acid chloride as a viscous oil. The crude acid chloride wasdissolved in methylene chloride (3 ml) and was cooled to 0° C. To thestirred solution was added 4-phenylsulfonylaniline (0.154 g, 0.66 mmol),triethylamine (0,067 g, 0.66 mmol) and dimethylaminopyridine (0.05 g).After stirring for 10 minutes the solution was allowed to warm to roomtemperature where it was stirred for a further 18 hours. The reactionmixture was then poured into water (10 ml). The organic layer was washedwith 3MHCl and brine. Drying (MgSO₄) and evaporation furnished agold-colored oil. Chromatography on silica gel, eluting with methylenechloride gave the title tertiary carbinol (0.10 g, 59%) as a tan solid;mp=103°-108° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 4.97 (s, 2H, CH₂), 7.41 (m,5M, ArH), 7.86 (m, 3H, ArH), 7.98 (m, 6H, ArH), 11.02 (s, 1H, NM). MS(CI, CH₄): 518(M+1, 50%).

Analysis for C₂₃ H₁₇ F₆ NO₄ S: Calculated: C, 67.76; H, 5.35; N, 4.65Found: C, 67.45; H, 5.41; N, 4.58

EXAMPLE 32N-[4-(Phenylsulfonyl)phenyl]-3,3,-difluoro-2-hydroxy-2-methylpropanamide.

A solution of 2-hydroxy-2-difluoromethylpropionic acid (0.9 g, 6.4 mmol)in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphereat -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and theresulting mixture was allowed to stir at -10° C. for 1 hour.4-Phenylsulfonylaniline (1.0 g, 4.3 mmol) was then added and thereaction mixture was stirred at -10° C. for a further 15 mins. Thesolution was then allowed to warm to room temperature where it wasstirred overnight. The reaction mixture was poured into ammoniumchloride solution and extracted with ethyl acetate. The combined ethylacetate fractions were washed with water and brine. After drying (Na₂SO₄) and decolorization (Charcoal) the solution was evaporated in vacuo.A foam was obtained which was triturated with toluene and crystallizedfrom ethyl acetate/hexane to give the title tertiary carbinol (0.72 g,47%) as white crystals; mp=168°-169° C. ^(H) -NMR (300 MHz, d₆ -DMSO):1.41 (s, 3H, CH3), 6.13 (t, J=54.9 Hz, 1H, CHF2), 6.76 (s, 1H, OH),7.58-7.68 (m, 3H, ArH), 7.89-8.01 (m, 6H, ArH), 10.27 (s, 1H, NH). MS(CI, CH₄): 356(M+1, 100).

Analysis for C₁₆ H₁₅ F₂ NO₄ S: Calculated: C, 54.08; H, 4.25; N, 3.94Found: C, 53.75; H, 4.40; N, 3.78

EXAMPLE 33N-[4-(Phenylcarbonyl)phenyl]-3,3,-difluoro-2-hydroxy-2-methylpropanamide.

A solution of 2-hydroxy-2-difluoromethylpropionic acid (1.07 g, 7.65mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogenatmosphere at -10° C. Thionyl chloride (0.91 g, 7.65 mmol) was added andthe resulting mixture was allowed to stir at -10° C. for 1 hour.4-Aminobenzophenone (1.0 g, 5.1 mmol) was then added and the reactionmixture was stirred at -10° C. for a further 15 mins. The solution wasthen allowed to warm to room temperature where it was stirred overnight.The reaction mixture was poured into hydrochloric acid solution (1M) andextracted with ethyl acetate. The combined ethyl acetate fractions werewashed with water and brine. After drying (Na₂ SO₄) and decolorization(Charcoal) the solution was evaporated in vacuo. A off-white foam wasobtained which was triturated with hexane/ethyl acetate. The crudeproduct was filtered through a short silica Eel column with chloroformand crystallized from chloroform/hexane to give the title tertiarycarbinol (0.89 g, 55%) as shiny, buff-colored crystals; mp=123°-124° C.¹ H-NMR (300 MHz, d₆ -DMSO): 1.45 (s, 3H, CH3), 6.17 (t, J=55 Hz, 1H,CHF2), 6.77 (s, 1H, OH), 7.56 (t, 2H, ArH), 7.65-7.76 (m, 5H, ArH), 7.96(d, J=8.7 Hz, 2H, ArH), 10.19 (s, 1H, NH). MS (CI, CH₄): 320(M+1, 100).

Analysis for C₁₇ H₁₅ F2NO₃. 0.2 H₂ O: Calculated: C, 63.23; H, 4.81; N,4.34 Found: C, 63.21; H, 4.74; N, 4.30

EXAMPLE 34N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propanamide.

Tetrahydrofuran (35 ml,dry) was added to a mixture of2,2-bis-trifluoromethyl 2-hydroxyacetic acid (1.08 g,5.1 mmol) and1,1'-carbonyldiimidazole (0.83 g,5.1 mmol), while under a nitrogenatmosphere. There was an immediate evolution of carbon dioxide. Thereaction was refluxed for 0.5 hrs and cooled to 23° C. The reaction wastreated with 4-aminobenzophenone (1.01 g,5.1 mmol), stirred at 23° C.for 1.5 hrs, and then at reflux 18 hrs. The reaction-was evaporated to ayellow oil-solid mixture. The mixture was dissolved in ethyl ether,treated with hydrogen chloride in ethyl ether, and filtered. Thefiltrate was evaporated to a yellow oil-solid mixture. Chromatography ofthis mixture on silica gel, eluting with 5% ethyl ether inmethylenechloride provided the title compound as an off-white solid; mp143°-146° C. ¹ H-NMR (250 MHz,d₆ -DMSO): 7.67(m, 2H, ArH), 7.83(m, 5H,ArH),7.96(d, j=8.8, 2H, ArH), 9.82(s, 1H, OH), 10.82(s, 1H, NH).MS(CI,CH₄): 392 (M+1).

Analysis for C₁₇ H₁₁ F₆ NO₃ : Calculated: C, 52.18; H, 2.83; N, 3.58Found: C, 52.25; H, 3.10; N, 3.50

2,2-bis-trifluoromethyl-2-hydroxyacetic acid was obtained from Fairfieldchemicals (custom synthesis).

EXAMPLE 35N-[4-[4-Pyridylsulfonyl)phenyl]]-3,3-difluoro-2-hydroxy-2-difluoromethyl-propanamide.

To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g,2.84 mmole) in dimethylacetamide (10 ml) at -10° C. was added thionylchloride (0.34 g, 2.84 mmol) dropwise. The resulting solution wasstirred at -10° C. for approximately 30 mins.4-(4-Pyridylsulfonyl)aniline (0.58 g, 2.5 mmol) was added and thereaction mixture was stirred overnight at room temperature. The reactionmixture was then poured into water, and sodium bicarbonate solution wasadded to give a pH of 7-7.5. A salmon pink colored precipitate wasformed. The solid was filtered, washed with water, and dried.Recrystallization and decolorization (charcoal) from ethylacetate/methanol/hexane gave the title compound (0.45 g, 46%) as a strawcolored solid; mp 248°-250° C. ¹ H-Nmr (300 MHz,d₆ -DMSO): 6.45(t,J=52.6 Hz, 2H, HCF₂), 7.88(d, J=6.1 Hz, 2H, ArH), 8.04(m, 5H, OH andArH), 8.86(s, J=6.1 Hz, 2H, ArH), 10.58(s, 1H, NH). MS(CI,CH₄): 393(M+1).

Analysis for C₁₅ H₁₂ F₄ N₂ O₄ S: Calculated: C, 45.92; H, 3.08; N, 7.14Found: C, 45.80; H, 3.13; N, 7.13

The 2,2-bis-difluoromethyl-2-hydroxyacetic acid was prepared as follows.

Trimethylsilyl cyanide (13.1 g, 0.13mole) was added dropwise to1,1,3,3-tetrafluoroacetone (17.17 g, 0.13mole) with stirring at atemperature of 0° C. The reaction flask was sealed and was kept at roomtemperature overnight. The clear reaction mixture was added dropwise toconcentrated sulfuric acid (60 ml). An exotherm was observed. Water (220mL) was then added dropwise and the resulting solution was stirred andrefluxed overnight. The reaction solution was cooled to roomtemperature, saturated with sodium chloride and extracted with ethylacetate (2×150 ml). The combined ethyl acetate extracts were dried (Na₂SO₄) and evaporated to give a syrup that slowly solidified to a whitesolid mass (12.8 g, 56%); mp 72.5°-73.5° C. ¹ H-NMR (300 MHz, d₆ DMSO):6.27 (s, 1H, OH), 6.26 (t, J=57.4 Hz, 2H, HCF₂). MS(CI): 177 (M+1,100%).

1,1,3,3-Tetrafluoroacetone was prepared using the procedure by W. J.Middleton and R. V. Lindsey, Jr., J. Am. Chem. Soc., 86, 4948(1964).

EXAMPLE 36N-[3-Hydroxy-4-(phenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred suspension ofN-[3-methoxy-4-(phenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide(0.75 g, 1.9 mmol) in dry methylene chloride (22 mL) was added borontribromide (3.8 mL of a 1.0M solution of boron tribromide in methylenechloride, 3.8 mmol). The resulting solution was stirred at roomtemperature for 3 hours, diluted with methylene chloride (50 mL) andwashed with water. The organic layer was dried (MgSO₄) and concentratedin vacuo to yield an off-white foam. Purification by flash columnchromatography (10% to 30% v/v ethyl acetate in methylene chloride)yielded the title propanamide as a white solid (0.34 g, 46%); mp155°-156° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 1.58 (s, 3H, CH₃) 7.30 (dd,1H, J=8.8,1.8 Hz, aromatic) 7.48 (s, 1H, OH) 7.51-1.66 (m, 4H, aromatic)7.80-7.86 (m, 3H, aromatic) 10.19 (s, 1H, NH)10.60 (s, 1H, OH). MS (CI,CH₄): 390 (M+1).

Analysis for C₁₆ H₁₄ F₃ NO₅ S: Calculated: C, 49.36; H, 3.62; N, 3.60.Found: C, 49.24; H, 3.58; N, 3.57.

EXAMPLE 37N-[3-Methoxy-4-(phenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.80 g, 11.4 mmol) inN,N-dimethylacetamide (40 mL) was added thionyl chloride (1.36 g, 11.4mmol) and the mixture stirred at -10° to -15° C. for 1 hour.3-Methoxy-4-(phenylulfonyl)benzeneamine (2.00 g, 7.6 mmol) was added inone portion and the reaction mixture stirred at room temperatureovernight. The mixture was poured into water and the aqueous solutionfiltered through a pad of Celite. The Celite was washed with methylenechloride (200 mL), the organic extract dried (MgSO₄), and the solventremoved in vacuo to yield a brown oil which was purified by flash columnchromatography (10% v/v ethyl acetate/methylene chloride). The resultingwhite solid (2.52 g, 82%) melted at 202-204° C. ¹ H-NMR (250 MHz, d₆-DMSO): 1.56 (s, 3H, CH₃) 3.8 (s, 3H, OCH₃) 7.70-7.54 (m, 6H,aromatic+OH) 7.85-7.88 (m, 2H, aromatic) 7.93 (d, 1H, J=8.7 Hz,aromatic) 10.32 (s, 1H, NH). MS (CI, CH₄): 404 (M+1).

Analysis for C₁₇ H₁₆ F₃ NO₅ S: Calculated: C, 50.62; H, 4.00; N, 3.47.Found: C, 50.38; H, 3.9; N, 3.44.

The starting benzeneamine was made as follows:

a. 3-Methoxy-4-(phenylsulfonyl)benzeneamine

A stirred solution of 2-methoxy-4-nitrodiphenylsulfone (6.15 g, 2.1mmol) and stannous chloride dihydrate (23.64 g, 10.5 mmol) in absoluteethanol (100 mL) was heated at reflux for 1 hour. The reaction mixturewas poured into ice water, and the aqueous solution basified with 15%NaOH and extracted with ethyl acetate (2×500 mL). The combined organicportions were dried (MgSO₄), filtered, and the solvent removed in vacuoto yield an off-white solid. Recrystallization from absolute ethanolyielded the title benzeneamine (4.49 g, 81%) as a white solid; mp149°-151° C. ¹ H-NMR (250 MHz, d6-DMSO): 3.61 (s, 3H, OCH₃) 6.14-6.15(3H, aromatic) 6.23 (dd, 1H, J=8.4, 1.9 Hz, aromatic) 7.50-7.60 (m, 4H,aromatic) 7.78-7.82 (m, 2H, aromatic). MS (CI, CH₄): 264 (M+1).

Analysis for C₁₃ H₁₃ NO₃ S: Calculated: C, 59.30; H, 4.98; N, 5.32.Found: C, 58.85; H, 5.00; N, 5.22.

b. 2-Methoxy-4-nitrodiphenylsulfone

To a stirred solution of 5-nitro-2-phenylthioanisole (8.27 g, 31.6 mmol)in glacial acetic acid (250 mL) was added potassium permanganate (6.00g, 38.0 mmol) in distilled water (100 mL). The dark brown mixture wasstirred at room temperature for 1 hour, then treated with solid sodiumsulfite until the solution clarified. The mixture was diluted with waterand filtered to yield a tan solid. Recrystallization from absoluteethanol yielded the title sulfone (7.71 g, 83%) as an off-white solid;173°-176° C. ¹ H-NMR (250 MHz, d₆ -DMSO): 3.89 (s, 3H, CH₃) 7.64 (t, 2H,J=7.4 Hz, aromatic) 7.74 (d, 1H, J=7.4 Hz, aromatic) 7.89 (d, 1H, J=2.0Hz, aromatic) 7.95 (d, 2H, J=7.4 Hz, aromatic) 8.02 (dd, 1H, J=8.6, 2.1Hz, aromatic) 8.30 (d, 1H, J=8.7 Hz, aromatic). MS (CI, CH₄): 294 (M+1).

Analysis for C₁₃ H₁₁ NO₅ S: Calculated: C, 53.24; H, 3.78; N, 4.78.Found: C, 52.96; H, 3.87; N, 4.76.

c. 5-Nitro-2-phenylthioanisole

A solution of 2-bromo-5-nitroanisole (10.00 g, 43.1 mmol) and potassiumphenylthiolate (6.12 g, 41.2 mmol) in dimethylformamide (50 mL) wasstirred at room temperature for 24 hours. The reaction mixture waspoured into ice water and filtered. The resulting solid wasrecrystallized from 95% ethanol to yield the title anisole (8.33 g, 74%)as a yellow solid; mp 89°-91° C. ¹ H-NMR (250 MHz, d6-DMSO): 4.02 (s,3H, OCH₃) 6.71-6.75 (m, 1H, aromatic) 7.56-7.61 (m, 5H, aromatic)7.74-7.78 (m, 2H, aromatic). MS (CI, CH₄): 262 (M+1).

Analysis for C₁₃ H₁₁ NO₃ S: Calculated: C, 59.76; H, 4.24; N, 5.36.Found: C, 59.79; H, 4.31; N, 5.14.

EXAMPLE 38N-[4-(Phenylsulfoxyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.09 g, 6.9 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.82 g, 6.9mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-Aminodiphenylsulfoxide (1.00 g, 4.6 mmol) was added in one portion andthe reaction mixture stirred at room temperature overnight. The mixturewas poured into water and the aqueous solution filtered through a pad ofCelite. The Celite was washed with methylene chloride (100 mL), theorganic extract dried (MgSO₄), filtered and the solvent removed in vacuoto yield a brown oil which was purified by flash column chromatography(10% v/v diethyl ether/methylene chloride). The resulting oil wasstirred with hexane and filtered to yield the title propanamide as awhite solid; mp 156°-158° C. ¹ H-NMR (300 MHz, d6-DMSO): 1.56 (s, 3H,CH₃) 7.49-7.56 (m, 4H, aromatic+OH) 7.65-7.70 (m, 4H, aromatic) 7.91 (d,2H, J=8.7 Hz, aromatic) 10.24 (s, 1H, NH). MS (CI, CH₄): 358 (M+1).

Analysis for C₁₆ H₁₄ F₃ NO₃ S: Calculated: C, 50.62; H, 4.00; N, 3.47.Found: C, 50.38; 3.97; N, 3.44.

4-Aminodiphenylsulfoxide is described in H. H. Szmant, J. J. McIntosh,J. Am. Chem. Soc., 73, 4356 (1951).

EXAMPLE 39N-[4-(2-Hydroxyphenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred suspension ofN-[4-(2-methoxyphenylsulfonyl)phenyl]3,3,3-trifluoro-2-hydroxy-2-methylpropanamide(1.14 g, 2.8 mmol) in dry methylene chloride (30 mL) was added borontribromide (8.5 mL of a 1.0M solution of boron tribromide in methylenechloride, 8.5 mmol). The resulting solution was stirred at roomtemperature for 3 hours, diluted with methylene chloride (50 mL) andwashed with water. The organic layer was dried (MgSO₄) and concentratedin vacuo to yield an off-white solid which was dissolved in ethylacetate (10 mL) and dropped into hexane (300 mL). Collection of theprecipitate by filtration yielded the title propanamide as a white solid(0.84 g, 77%); mp 184°-186° C. ¹ H-NMR (250 MHz, d6-DMSO): 1.57 (s, 3H,CH₃) 6.90 (d, 1H, J=8.3 Hz, aromatic) 7.01 (t, 1H, J=7.5 Hz, aromatic)7.50 (m, 1H, aromatic) 7.56 (s, 1H, OH) 7.85-7.97 (m, 5H, aromatic)10.37 (s, 1H, NH) 10.74 (s, 1H, OH). MS (CI, CH₄): 390 (M+1).

Analysis for C₁₆ H₁₄ F₃ NO₅ S: Calculated: C, 49.36; H, 3.62; N, 3.60.Found: C, 49.34; H, 3.83; N, 3.42.

EXAMPLE 40N-[4-(2-Methoxyphenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-hydroxy-2-methylpropanoic acid (1.42 g, 9.0 mmol) inN,N-dimethylacetamide (13 mL) was added thionyl chloride (1.13 g, 9.5mmol) and the mixture stirred at -15° to -5° C. for 1 hour.4-(2-Methoxyphenyl)sulfonyl-benzeneamine (1.58 S, 6.0 mmol) was added inone portion and the reaction mixture stirred at room temperatureovernight. The mixture was poured into 250 mL of 0.5N HCl. The clearsupernatent was decanted from the resulting gum. The gum wascrystallized from methylene chloride/hexane to yield the titlepropanamide which contained about 10 mole % of methylene chloride by NMRanalysis. The methylene chloride was not removed by heating at 140°/0.1mm for 40 hours. The yield of white solid was 1.70 g (69%), mp 209°-211°C. ¹ H-NMR (300 MHz, d6-DMSO): 1.55 (s, 3H, CH₃) 3.72 (s, 3H, OCH₃) 5.73(s, CH₂ Cl) 7.11-7.17 (m, 2H, aromatic) 7.53 (s, 1H, OH) 7.60-7.63 (m,1H, aromatic) 7.80-7.83 (m, 2H, aromatic) 0.92-7.97 (m, 3H, aromatic)10.36 (s, 1H, NH). MS (CI, CH₄): 294 (M+1).

Analysis for C₁₇ H₁₆ F₃ NO₅ S. 0.1 CH₂ Cl₂ : Calculated: C, 49.87; H,3.96; N, 3.40. Found: C, 49.71; H, 3.96; N, 3.35.

The starting benzeneamine was made as follows:

a. 4-(2-Methoxyphenyl)sulfonylbenzeneamine

To a stirred slurry of 2-methoxy-4'-nitrodtphenylsulfone (12.36 g, 4.2mmol) in absolute ethanol (90 mL) was added in one portion stannouschloride dihydrate (47.4 g, 21 mmol) and the mixture heated to 50° C.where an exothermic reaction occurred. The reaction mixture was stirredat ambient temperature for 30 minutes, poured into ice water, theaqueous solution basified with 15% NaOH and extracted with methylenechloride (3×275 mL). The combined organic portions were dried (MgSO₄),filtered, and the solvent removed in vacuo to yield a white solid.Recrystallization from ethyl acetate yielded the title benzeneamine(5.38 g, 49%) as a white solid; mp 206°-208° C. ¹ H-NMR (300 MHz,d6-DMSO): 3.75 (s, 3H, OCH₃) 6.10 (s, 2H, NH₂) 6.56-6.61 (m, 2H,aromatic) 7.08-7.13 (m, 2H, aromatic) 7.49-7.61 (m, 3H, aromatic) 7.91(dd, 1H, J=8.2 Hz, J=1.8 Hz, aromatic). MS (CI, CH₄): 264 (M+1).

Analysis for C₁₃ H₁₃ NO₃ S: Calculated: C, 59.30;H, 4.98;N, 5.32. Found:C, 59.28; H, 5.04; N, 5.20.

b. 2-Methoxy-4'-nitrodiphenylsulfone

To a stirred solution of 2-methoxy-4'-nitrodiphenylsulfide (13.73 g,52.5 mmol) in glacial acetic acid (800 mL) was added potassiumpermanganate (9.97 g, 63 mmol) in distilled water (350 mL). The darkbrown mixture was stirred at room temperature for 45 minutes, pouredinto 2 L of water, treated with solid sodium sulfite until the solutionclarified and the solid collected by filtration. Recrystallization twicefrom absolute ethanol (300 mL) yielded the title sulfone (7.71 g, 83%)as white plates; mp 140°-142° C. ¹ H-NMR (300 MHz, CDCl₃): 3.79 (s, 3H,CH₃) 6.94 (d, 1H, J=8.4 Hz, aromatic) 7.16 (t, 1H, J=7.6 Hz, aromatic)7.58-7.64 (m, 1H, aromatic) 8.13-8.19 (m, 3H, aromatic) 8.31-8.35 (m,2H, aromatic). MS (CI, CH₄): 294 (M+1).

Analysis for C₁₃ H₁₁ NO₅ S: Calculated: C, 53.24; H, 3.78; N, 4.78.Found: C, 52.23; H, 3.79; N, 4.79.

c. 2-Methoxy-4'-nitrodiphenylsulfide

A solution of 1-chloro-4-nitrobenzene (11.23 g, 71.3 mmol) and potassium2-methoxybenzenethiolate [from 2-methoxythiophenol (10.00 g, 71.3 mmol)and potassium hydroxide (4.00 g 71.3 mmol)] in dimethylformamide (90 mL)was stirred at room temperature for 18 hours. The reaction mixture waspoured into ice water, stirred for 1 hour and filtered. The resultingsolid was recrystallized once from 85% ethanol (150 mL) and twice fromhexane (700 mL) to yield the title sulfide (13.83 g, 74%) as pale yellowneedles; mp 90°-92° C. ¹ H-NMR (300 MHz, CDCl₃): 3.82 (s, 3H, OCH₃)7.01-7.15 (m, 4H, aromatic) 7.46-7.55 (m, 2H, aromatic) 8.02-8.07 (m,2H, aromatic). MS (CI, CH₄): 262 (M+1).

Analysis for C₁₃ H₁₁ NO₃ S: Calculated: C, 59.76; H, 4.24; N, 5.36.Found: C, 59.70; H, 4.25; N, 4.71.

EXAMPLE 41N-[4-(4-Fluorophenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.94 g, 6.0 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.71 g, 6.0mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-(4-Fluorophenylsulfonylbenzeneamine (1.00 g, 4.0 mmol) was added inone portion and the reaction mixture stirred at room temperatureovernight. The mixture was poured into water and the aqueous solutionfiltered to yield a brown solid. Purification by flash columnchromatography (5% v/v ethyl acetate/methylene chloride)-yielded thetitle propanamide as a white solid (1.11 g, 71%); mp 168°-170° C. ¹H-NMR (300 MHz, d6-DMSO): 1.57 (s, 3H, CH₃) 7.46 (t, 2H, J=8.8 Hz,aromatic) 7.57 (s, 1H, OH) 7.93 (d, 2H, J=8.8 Hz, aromatic) 7.99-8.04(m, 4H, aromatic) 10.43 (s, 1H, NH). MS (CI, CH₄): 392 (M+1).

Analysis for C₁₆ H₁₃ F₄ NO₄ S: Calculated: C, 49.11; H, 3.35; N, 3.58.Found: C, 48.92; H, 3.37; N, 3.45.

4-[(4-Fluorophenyl)sulfonyl]benzeneamine is described in N. Sharghi, I.Lalezari, J. Chem. Eng. Data, 8, 276, (1963).

EXAMPLE 42N-[4-(3-Fluorophenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.94 g, 6.0 mmol) inN,N-dimethylaceamide (10 mL) was added thionyl chloride (0.71 g, 6.0mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-(3-Fluorophenylsulfonylbenzeneamine (1.00 g, 4.0 mmol) was added inone portion and the reaction mixture stirred at room temperatureovernight. The mixture was poured into water and the aqueous solutionfiltered to yield a brown solid which was purified by flash columnchromatography (5% v/v ethyl acetate/methylene chloride). Trituration ofthe resulting solid with ethyl ether yielded the title propanamide as awhite solid (1.15 g, 73%); mp 147°-148° C. ¹ H-NMR (300 MHz, d6-DMSO):1.57 (s, 3H, CH₃) 7.56-7.58 (m, 2H, aromatic+OH) 7.68-7.69 (m, 1H,aromatic) 7.78-7.82 (m, 2H, aromatic) 7.97 (d, 2H, J=8.9 Hz, aromatic)8.03 (d, 2H, J=9.1, aromatic) 10.45 (s, 1H, NH). MS (CI, CH₄): 392(M+1).

Analysis for C₁₆ H₁₃ F₄ NO₄ S: Calculated: C, 49.11; H, 3.35; N, 3.58.Found: C, 49.03; H, 3.43; N, 3.50.

4-(3-Fluorophenyl)sulfonylbenzeneamine is described in N. Sharghi, I.Lalezari, J. Chem. Eng. Data, 8, 276, (1963).

EXAMPLE 43N-[4-(3-Hydroxyphenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred suspension ofN-[4-(3-methoxyphenylsulfonyl)-phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide(1.25 g, 3.1 mmol) in dry methylene chloride (30 mL) was added borontribromide (9.3 mL of a 1.0M solution of boron tribromide in methylenechloride, 9.3 mmol). The resulting solution was stirred at roomtemperature for 2 hours, diluted with methylene chloride (50 mL) andwashed with water. The organic layer was dried (MgSO₄) and concentratedin vacuo. The resulting tan solid was triturated with methylene chlorideto yield the title propanamide as a white solid (0.98 g, 78%); mp164°-167° C. ¹ H-NMR (300 MHz, d6-DMSO): 1.57 (s, 3H, CH₃) 7.00-7.04 (m,1H, aromatic) 7.24 (t, 1H, J=1.6 Hz, aromatic) 7.31-7.40 (m, 2H,aromatic) 7.55 (s, 1H, OH) 7.89 (d, 2H, J=8.9 Hz, aromatic) 8.00 (d, 2H,J=9.0 Hz, aromatic) 10.22 (s, 1H, NH), 10.41 (s, 1H, ArOH). MS (CI,CH₄): 390 (M+1).

Analysis for C₁₆ H₁₄ F₃ NO₅ S. 0.50 H₂ O: Calculated: C, 48.20; H, 3.51;N, 3.51. Found: C, 47.98; H, 3.71; N, 3.44.

EXAMPLE 44N-[4-(3-Methoxyphenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1. [680 g, 11.4 mmol)in N,N-dimethyl-acetamide (10 mL) was added thionyl chloride (1.36 g,11.4 mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-[(3-Methoxy-phenyl)sulfonyl]-benzeneamine (2.00 g, 7.6 mmol) was addedin one portion and the reaction mixture stirred at room temperatureovernight. The mixture was poured into water and the aqueous solutionfiltered to yield a brown solid. Purification by flash columnchromatography (10% v/v ethyl acetate/methylene chloride) yielded thetitle propanamide as a white solid (2.75 g, 90%); mp 147°-148° C. ¹H-NMR (300 MHz, d6-DMSO): 1.58 (s, 3H, CH₃) 3.83 (s, 3H, OCH₃) 7.22-7.25(m, 1H, aromatic) 7.41-7.42 (m, 1H, aromatic) 7.47-7.56 (m, 3H,aromatic+OH) 7.93-8.01 (m, 4H, aromatic) 10.42 (s, 1H, NH). MS (CI,CH₄): 404 (M+1).

Analysis for C₁₇ H₁₆ F₃ NO₅ S: Calculated: C, 50.62; H, 3.40; N, 3.47.Found: C, 50.14; H, 3.40; N, 3.40.

a. 4-[(3-Methoxyphenyl)sulfonyl]benzeneamine

A stirred solution of 3-methoxy-4'-nitrodiphenylsulfone (7.56 g, 25.8mmol) and stannous chloride dihydrate (29.06 g, 129 mmol) in absoluteethanol (50 mL) was heated at reflux for 1 hour. The reaction mixturewas poured into ice water, the aqueous solution basified with 15% Na₀ Hand extracted with ethyl acetate (2×200 mL). The combined organicportions were dried (MgSO₄), filtered, and the solvent removed in vacuoto yield an off-white solid. Recrystallization from absolute ethanolyielded the title benzeneamine (4.63 g, 68%) as a white solid; mp116°-117° C. ¹ H-NMR (300 MHz, d₆ -DMSO): 3.81 (s, 3H, OCH₃) 6.20 (s,2H, NH₂) 6.62-6.66 (m, 2H, aromatic) 7.15-7.19 (m, 1H, aromatic +OH)7.32-7.60 (m, 5H, aromatic). MS (CI, CH₄): 264 (M+1).

Analysis for C₁₃ H₁₃ NO₃ S: Calculated: C, 59.30; H, 4.98; N, 5.32.Found: C, 59.11; H, 5.04; N, 5.28.

b. 3-Methoxy-4'-nitrodiphenylsulfone

To a stirred solution of 3-(4-nitrophenylthio)anisole (7.79 g, 29.8mmol) in glacial acetic acid (200 mL) was added potassium permanganate(5.65 g, 35.8 mmol) in distilled water (75 mL). The dark brown mixturewas stirred at room-temperature for 1 hour, then treated with solidsodium sulfite until the solution clarified. The mixture was dilutedwith water and filtered to yield a tan solid. Recrystallization fromabsolute ethanol yielded the title sulfone (7.56 g, 86%) as an off-whitesolid; mp 123°-125° C. ¹ H-NMR (250 MHz, d6-DMSO): 3.86 (s, 3H, OCH₃)7.29-7.33 (m, 1H, aromatic) 7.51 (br s, 1H, aromatic) 7.59 (d, 2H, J=3.8Hz, aromatic) 8.27 (dd, 2H, J=7.0, 1.9 Hz, aromatic) 8.39 (dd, 2H,J=7.0, 1.9 Hz, aromatic). MS (CI, CH₄): 294 (M+1).

Analysis for C₁₃ H₁₁ NO₅ S: Calculated: C, 53.24; H, 3.78; N, 4.78.Found: C, 53.19; H, 3.85; N, 4.90.

c. 3-(4-Nitrophenylthio)anisole

A solution of potassium 3-methoxybenzenethiolate (6.37 g, 35.7 mmol) and4-chloronitrobenzene (5.11 g, 32.5 mmol) in dimethylformamide (30 mL)was stirred at room temperature for 4 hours. The reaction mixture waspoured into ice water and a yellow solid was collected by filtration.Recrystallization from 90% ethanol yielded the title anisole (7.79 g,92%) as a yellow solid; mp 81°-83° C. ¹ H-NMR (250 MHz, d6-DMSO): 3.80(s, 3H, OCH₃) 7.10-7.19 (m, 3H, aromatic) 7.32 (d, 2H, J=7.1 Hz,aromatic) 7.43-7.49 (m, 1H, aromatic) 8.15 (d, 2H, J=7.0, aromatic). MS(CI, CH₄): 262 (M+1).

Analysis for C₁₃ H₁₁ NO₃ S: Calculated: C, 59.76; H, 4.24; N, 5.36.Found: C, 59.74; H, 4.40; N, 5.34.

EXAMPLE 45N-[3-Methyl-4-(phenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.72 g, 4.5 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.54 g, 4.5mmol) and the mixture stirred at -10° to -15° C. for 1 hour.3-Methyl-4-(phenylsulfonyl)-benzeneamine (0.75 g, 3.0 mmol) was added inone portion and the reaction mixture stirred at room temperatureovernight. The mixture was poured into water and the aqueous solutionfiltered to yield a brown solid which was purified by flash columnchromatography (5% v/v ethyl acetate/methylene chloride). Trituration ofthe resulting solid with hexane yielded the title propanamide as a whitesolid (0.95 g, 82%); mp 141°-143° C. ¹ H-NMR (300 MHz, d6-DMSO): 1.58(s, 3H, CH₃) 2.32 (s, 3H, ArCH₃) 7.55-7.70 (m, 4H, aromatic) 7.79-7.85(m, 3H, aromatic) 7.92 (dd, 1H, J=8.8, 1.9 Hz, aromatic) 8.10 (d, 1H,J=8.8 Hz, aromatic) 10.30 (s, 1H, NH). MS (CI, CH₄): 388 (M+1).

Analysis for C₁₇ H₁₆ F₃ NO₄ S: Calculated: C, 52.71; H, 4.16; N, 3.62.Found: C, 52.59; H, 4.24; N, 3.59.

The starting benzeneamine was made as follows:

a. 3-Methyl-4-(phenylsulfonyl)benzeneamine

A stirred solution of 2-methyl-4-nitrodiphenylsulfone (2.72 g, 9.8 mmol)and stannous chloride dihydrate (11.06 g, 49.0 mmol) in absolute ethanol(30 mL) was heated at reflux for 1 hour. The reaction mixture was pouredinto ice water, the aqueous solution basified with 15% NaOH andextracted with ethyl acetate (2×100 mL). The combined organic portionshere dried (MgSO₄), filtered, and the solvent removed in vacuo to yieldan off-white solid. Recrystallization from ethyl acetate yielded thetitle benzeneamine (2.12 g, 88%) as a white solid; mp 163°-165° C. ¹H-NMR (300 MHz, d6-DMSO): 2.17 (s, 3H, ArCH₃) 6.10 (s, 2H, NH₂) 6.38 (d,1H, J=2.1 Hz, aromatic) 6.53 (dd, 1H, J=8.7, 2.2 Hz, aromatic) 7.54-7.62(m, 4H, aromatic) 7.73-7.77 (m, 2H, aromatic). MS (CI, CH₄): 248 (M+1).

Analysis for C₁₃ H₁₃ NO₂ S: Calculated: C, 63.14; H, 5.30; N, 5.66.Found: C, 63.10; H, 5.30; N, 5.62.

b. 2-Methyl-4-nitrodiphenylsulfone

To a stirred solution of 2-phenylthio-5-nitrotoluene (3.24 g, 13.2 mmol)in glacial acetic acid (70 mL) was added potassium permanganate (2.50 g,15.8 mmol) in distilled water (30 mL). The dark brown mixture wasstirred at room temperature for 2 hour, then treated with solid sodiumsulfite until the solution clarified. The mixture was diluted with waterand filtered to yield an off-white solid. Recrystallization from 95%ethanol yielded the title sulfone (2.75 g, 75%) as an off-white solid;mp 113°-114° C. ¹ H-NMR (250 MHz, d6-DMSO): 2.48 (s, 3H, ArCH₃)7.63-7.80 (m, 3H, aromatic) 7.92 (d, 2H, J=7.4 Hz, aromatic) 8.25-8.38(m, 3H, aromatic). MS (CI, CH₄): 278 (M+1).

Analysis for C₁₃ H₁₁ NO₅ S: Calculated: C, 56.31; H, 4.00; N, 5.05.Found: C, 56.10; H, 4.14; N, 4.95.

2-Phenylthio-5-nitrotoluene is described in A. B. Sakla, et. al., Acta.Chim. Acad. Sci. Hung. 98 (4), 479 (1978). Chem. Abstr 90: 203595d.

EXAMPLE 46N-[4-(2-Fluorophenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.10 g, 7.0 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.83 g, 7.0mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-Amino-2'-fluoro benzophenone (1.00 g, 4.6 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The mixture was poured into water and the aqueous solution filtered toyield a brown solid. Purification by flash column chromatography (5% v/vethyl acetate/methylene chloride) yielded the title propanamide as awhite solid (1.23 g, 75%); mp 141°-142° C. ¹ H-NMR (300 MHz, d₆ -DMSO):1.60 (s, 3H, CH₃) 7.35-7.42 (m, 2H, aromatic) 7.53-7.59 (m, 2H, aromatic+OH) 7.65-7.68 (m, 1H, aromatic) 7.75 (d, 2H, J=8.5 Hz, aromatic) 7,96(dd, 2H, J=8.6, 1.7 Hz, aromatic) 10.37 (s, 1H, NH). MS (CI, CH₄): 356(M+1).

Analysis for C₁₇ H₁₃ F₄ NO₃ : Calculated: C, 57.47; H, 3.69; N, 3.94.Found: C, 57.44; H, 3.77; N, 3.91.

The starting benzophenone was made as follows:

a. 4-Amino-2'-fluorobenzophenone

To stirred 90° C. polyphosphoric acid (200 g) was added 14.29 g (10.2mmol) of 2-fluorobenzoic acid and aniline (9.32 g 10.0 mmol) and thebath temperature raised to 180°-190° C. and held there for 1 hour. Asolution was obtained at about 140° C. The heating bath was removed andthe stirred mixture (sublimate above the solution) was treatedcautiously with 80 mL of water. The mixture was stirred at 140°-155° C.for 1 hour, the heating bath removed, 66 mL of 3N HCl added, the mixturepoured into 1 L of water and filtered through a pad of Celite. Thefiltrate was basified with 15% sodium hydroxide and the solid whichformed on stirring was collected. The Celite pad was washed well withmethylene chloride, the methylene chloride removed and the residue wascombined with the solid obtained from basification of the aqueous phase.The combined material was dissolved in refluxing ethanol (175 mL), andtreated hot with 125 mL of water. The brown solid obtaing on cooling wasadditionally recrystallized twice from ethyl acetate-hexane. Finalpurification by flash column chromatography (methylene chloride) yieldedthe aniline as a white solid (5.45 g, 25%); mp 128°-130° C. ¹ H-NMR (250MHz, d₆ -DMSO): 6.32 (s, 2H, NH₂) 6.60 (dd, 2H, J=8.6, 1.5 Hz, aromatic)7.28-7.35 (m, 2H, aromatic) 7.40-7.60 (m, 4H, aromatic). MS (CI, CH₄):216 (M+1).

Analysis for C₁₃ H₁₀ FNO: Calculated: C, 72.55; H, 4.68; N, 6.51. Found:C, 72.46; H, 4.82; N, 6.21.

EXAMPLE 47

N-[3-Hydroxy-4-(4-pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred suspension ofN-[3-methoxy-4-(4-pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide(1.05 g, 2.6 mmol) in dry methylene chloride (30 mL) was added borontribromide (10.4 mL of a 1.0M solution of boron tribromide in methylenechloride, 10.4 mmol). The resulting solution was stirred at reflux for 2hours. An additional 5 mL of 1.0M boron tribromide solution in methylenechloride was added and the reaction stirred overnight at roomtemperature. The reaction mixture was diluted with methylene chloride(50 mL) and washed with water. The organic layer was dried (MgSO₄) andconcentrated in vacuo to yield an oil. Purification by flash columnchromatography (20% v/v methanol in ethyl acetate) yielded the titlepropanamide as a white solid (0.18 g, 18%); mp 188°-189° C. ¹ H-NMR (250MHz, d6-DMSO): 1.54 (s, 3H, CH₃) 7.35 (d, 1H, J=9.0 Hz, aromatic) 7.51(s, 1H, OH) 7.61 (s, 1H, aromatic) 7.77 (d, 2H, J=5.5 Hz, aromatic) 7.84(d, 1H, J=8.9 Hz, aromatic) 8.83 (d, 2H, J=5.5 Hz, aromatic) 10.26 (s,1H, NH) 11.04 (s, 1H, ArOH). MS (CI, CH₄): 391 (M+1).

Analysis for C15H₁₃ F₃ N₂ O₅ S. 0.25 H₂ O: Calculated: C, 45.63; H,3.44; N, 7.09. Found: C, 45.51; H, 3.58; N, 6.98.

EXAMPLE 48N-[3-Methoxy-4-(4-pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.79 g, 11.3 mmol) inN,N-dimethylacetamide (20 mL) was added thionyl chloride (1.34 g, 11.3mmol) and the mixture stirred at -10° to -15° C. for 1 hour.3-Methoxy-4-(4-pyridylsulfonyl)benzeneamine (2.00 g, 7.6 mmol) was addedin one portion and the reaction mixture stirred at room temperatureovernight. The mixture was poured into water and the aqueous solutionfiltered through Celite. The Celite was washed with methylene chloride(100 mL), the methylene chloride solution dried (MgSO₄) and concentratedin vacuo to an off-white solid. Trituration with ethyl ether yielded thetitle propanamide as a white solid (1.65 g, 54%); mp 238°-240° C. ¹H-NMR (250 MHz, d6-DMSO): 1.58 (s, 3H, CH₃) 3.70 (s, 3H, OCH₃) 7.60 (s,1H, OH) 7.71 (d, 1H, J=4.6 Hz, aromatic) 7.75-7.79 (m, 3H, aromatic)7.96 (d, 1H, J=8.8 Hz, aromatic) 8.85 (dd, 2H, J=4.6, 1.1 Hz, aromatic)10.39 (s, 1H, NH). MS (CI, CH₄): 405 (M+1).

Analysis for C₁₆ H₁₅ F₃ N₂ O₅ S: Calculated: C, 47.53; H, 3.74; N, 6.93;Found: C, 47.45; H, 3.79; N, 6.79;

The starting benzeneamine was made as follows:

a. 3-Methoxy-4-(4-pyridylsulfonyl)benzeneamine

A stirred solution of 5-nitro-2-(4-pyridylsulfonyl)anisole (3.00 g, 10.2mmol) and stannous chloride dihydrate (11.49 g, 51.0 mmol) in absoluteethanol (35 mL) was heated at reflux for 1 hour. The reaction mixturewas poured into ice water, and the aqueous solution basified with 15%NaOH and extracted with ethyl acetate (2×200 mL). The combined organicportions were dried (MgSO₄) and the solvent removed in vacuo to yieldthe title benzeneamine as a pale yellow solid (2.23 g, 83%); mp150°-152° C. ¹ H-NMR (250 MHz, d6-DMSO): 3.62 (s, 3H, OCH₃) 6.18 (d, 1H,J=1.8 Hz, aromatic) 6.24 (d, 1H, J=1.9 Hz, aromatic) 6.28 (s, 2H, NH₂)7.58 (d, 1H, J=8.8 Hz, aromatic) 7.70 (dd, 2H, J=4.5, 1.5 Hz, aromatic)8.79 (dd, 2H, J=4.4, 1.6 Hz, aromatic). MS (CI, CH₄): 265 (M+1).

Analysis for C₁₂ H₁₂ N₂ O₃ S: Calculated: C, 54.53; H, 4.58; N, 10.60.Found: C, 54.36; H, 5.56; N, 10.44.

b. 5-Nitro-2-(4-pyridylsulfonyl)anisole

To a stirred solution of-5-nitro-2-(4-pyridylthio)anisole (5.00 g, 19.1mmol) in glacial acetic acid (150 mL) was added potassium permanganate(3.61 g, 22.9 mmol) in distilled water (75 mL). The dark brown mixturewas stirred at room temperature for 1 hour, then treated with solidsodium sulfite until the solution clarified. The mixture was dilutedwith water and filtered to yield a brown solid. Recrystallization fromabsolute ethanol yielded the title sulfone (3.63 g, 65%) as a tan solid;mp 173°-175° C. ¹ H-NMR (250 MHz, d6-DMSO): 3.90 (s, 3H, OCH₃) 7.90-7.94(m, 3H, aromatic) 8.06 (d, 1H, J=7.8 Hz, aromatic) 8.33 (d, 1H, J=7.9Hz, aromatic) 8.92 (br s, 2H, aromatic). MS (CI, CH₄): 295 (M+1).

Analysis for C₁₂ H₁₀ N₂ O₅ S. 0.5 H₂ O: Calculated: C, 48.24; H, 3.54;N, 9.38 Found: C, 48.20; H, 3.48; N, 9.46

c. 5-Nitro-2-(4-pyridylthio)anisole

A solution of potassium 4-pyridinethiolate (20.00 g, 134 mmol) and2-chloro-5-nitroanisole (20.91 g, 112 mmol) in dimethylformamide (80 mL)was stirred at room temperature for 24 hours. The reaction mixture waspoured into ice water and a brown solid was collected by filtration. Thesolid was stirred with 3N HCl (400 mL) for 30 minutes, and the solutionfiltered. The filtrate was basified with ammonium hydroxide with coolingin an ice bath. Filtration of the basic solution yielded the titleanisole as an orange solid (26.23 g, 90%); mp 133°-135° C. ¹ H-NMR (300MHz, d6-DMSO): 3.95 (s, 3H, OCH₃) 7.24 (dd, 2H, J=4.6, 1.7 Hz, aromatic)7.53 (d, 1H, J=8.3 Hz, aromatic) 7.88 (dd, 2H, J=8.3, 2.3 Hz, aromatic)8.48 (dd, 2H, J=4.7, 1.3 Hz, aromatic). MS (CI, CH₄): 263 (M+1).

Analysis for C₁₂ H₁₀ N₂ O₃ S: Calculated: C, 54.95; H, 3.84; N, 10.68.Found: C, 54.81; H, 3.92; N, 10.70.

EXAMPLE 49N-[3-Fluoro-4-(phenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.71 g, 4.5 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.54 g, 4.5mmol) and the mixture stirred at -10° to -15° C. for 1 hour.3-Fluoro-4-(phenyl sulfonyl)benzeneamine (0.75 g, 3.0 mmol) was added inone portion and the reaction mixture stirred at room temperatureovernight. The mixture was poured into water and the aqueous solutionfiltered through Celite. The Celite was washed with methylene chloride(75 mL), the organic extract dried (MgSO₄) and concentrated in vacuo toa tan solid. Purification by flash column chromatography (5% v/v ethylacetate/methylene chloride) yielded the title propanamide as a whitesolid (0.79 g, 68%); mp 147°-149° C. ¹ H-NMR (250 MHz, d6-DMSO): 1.58(s, 3H, CH₃) 7.65-7.69 (m, 4H, aromatic+OH) 7.74 (d, 1H, J=7.2 Hz,aromatic) 7.83-7.94 (m, 3H, aromatic) 8.02 (t, 1H, J=8.3 Hz, aromatic)10.61 (s, 1H, NH). MS (CI, CH₄): 392 (M+1).

Analysis for C₁₆ H₁₃ F₄ NO₄ S: Calculated: C, 49.12; H, 3.35; N, 3.58.Found: C, 48.91; H, 3.28; N, 3.53.

The starting benzeneamine was made as follows:

a. 3-Fluoro-4-(phenylsulfonyl)benzeneamine

A stirred solution of 2-fluoro-4-nitrodiphenylsulfone (4.78 g, 17.0mmol) and stannous chloride dihydrate (21.62 g, 95.9 mmol) in absoluteethanol (50 mL) was heated at reflux for 1 hour. The reaction mixturewas poured into ice water, and the aqueous solution basified with 15%NaOH and extracted with ethyl acetate (3×200 mL). The combined organicportions were dried (MgSO₄), filtered and the solvent removed in vacuoto yield an off-white solid. Recrystallization from absolute ethanolyielded the title benzeneamine (3.43 g, 80%) as a white solid; mp161°-163° C. ¹ H-NMR (250 MHz, d6-DMSO): 6.32 (dd, 1H, J=13.5, 1.8 Hz,aromatic) 6.47 (d, 1H, J=2.0 Hz, aromatic) 6.50 (s, 2H, NH₂) 7.59-7.67(m, 4H, aromatic) 7.85 (d, 2H, J=7.6 Hz, aromatic). MS (CI, CH₄): 252(M+1). Analysis for C₁₂ H₁₀ NO₂ S: Calculated: C, 57.36; H, 4.01; N,5.57 Found: C, 57.27; H, 4.15; N, 5.58. b.2-Fluoro-4-nitrodiphenylsulfone

To a stirred solution of 3-fluoro-4-(phenylthio)nitrobenzene (5.65 g,22.7 mmol) in glacial acetic acid (200 mL) was added potassiumpermanganate (4.30 g, 27.2 mmol) in distilled water (75 mL). The darkbrown mixture was stirred at room temperature for 1 hour, then treatedwith solid sodium sulfite until the solution clarified. The mixture wasdiluted with water and filtered to yield an off-white solid.Recrystallization from absolute ethanol yielded the title sulfone (4.80g, 75%) as an off-white solid; mp 124°-125° C. ¹ H-NMR (300 MHz,DMSO-d6): 7.68-7.73 (m, 2H, aromatic) 7.79-7.84 (m, 1H, aromatic) 8.00(d, 2H, J=8.2 Hz, aromatic) 8.28-8.38 (m, 3H, aromatic). MS (CI, CH₄):282 (M+1).

Analysis for C₁₂ H₈ NO₄ S: Calculated: C, 51.25; H, 2.87; N, 4.98.Found: C, 51.30; H, 2.87; N, 4.53. C.3-Fluoro-4-(phenylthio)nitrobenzene

A solution of potassium phenylthiolate (9.50 g, 64.1 mmol) and3,4-difluoronitrobenzene (10.00 g, 64.1 mmol) in dimethylform- amide (40mL) was stirred at room temperature for 24 hours. The reaction mixturewas poured into ice water and a yellow solid was collected byfiltration. Recrystallization from 95% ethanol yielded the title sulfide(10.68 g, 67%) as a yellow solid; mp 54°-55° C. ¹ H-NMR (250 MHz,d6-DMSO): 7.03 (t, 1H, J=7.8 Hz, aromatic) 7.52-7.62 (m, 5H, aromatic)8.00 (dd, 1H, J=8.9, 2.3 Hz, aromatic) 8.17 (dd, 1H, J=8.8, 2.3 Hz,aromatic). MS (CI, CH₄): 250 (M+1).

Analysis for C₁₂ H₈ NO₂ S: Calculated: C, 57.82; H, 3.23; N, 5.62.Found: C, 57.71; H, 3.21; N, 5.35.

EXAMPLE 50N-[4-(2,5-Difluorophenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.95 g, 6.0 mmol) inN,N-dimethylacetamide (15 mL) was added thionyl chloride (0.72 g, 6.0mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4'-Amino-2,5-difluoro benzophenone (1.00 g, 4.3 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The mixture was poured into water and the aqueous solution filtered toyield a brown solid. Recrystallization from methylene chloride/hexaneyielded the title propanamide as a white solid (1.03 g, 69%); mp145°-147° C. ¹ H-NMR (250 MHz, d6-DMSO): 1.59 (s, 3H, CH₃) 7.44-7.47 (m,3H, aromatic) 7.57 (s, 1H, OH) 7.77 (d, 2H, J=8.0 Hz, aromatic) 7.97 (d,2H, J=8.0 Hz, aromatic) 10.40 (s, 1H, NH). MS (CI, CH₄): 374 (M+1).

Analysis for C₁₇ H₁₂ F₅ NO₃ : Calculated: C, 54.70; H, 3.24; N, 3.75.Found: C, 54.29; H, 3.16; N, 3.72.

The starting benzophenone was made as follows:

a. 4'-Amino-2,5-difluorobenzophenone

To stirred 90° C. polyphosphoric acid (125 g) was added2,5-difluoro-benzoic acid (10.0 g, 6.32 mmol) and aniline (5.87 g 6.3mmol) and the bath temperature raised to 180°-190° C. and held there for1 hour. The heating bath was removed and the stirred mixture (sublimateabove the solution) was treated cautiously with 50 mL of water. Themixture was stirred at 140°-155° C. for 1 hour, the heating bathremoved, 45 mL of 3N HCl added, the mixture poured into 650 mL of waterand filtered through a pad of Celite. The filtrate was basified with 15%sodium hydroxide and the mixture filtered through a pad of Celite. TheCelite pad was washed well with methylene chloride, the methylenechloride dried (MgSO₄), filtered and the solvent removed in vacuo.Purification by flash column chromatography (methylene chloride)followed by recrystallization twice from 50% ethanol (80 mL) yielded theaniline as a yellow solid (3.08 g, 21%); mp 101°-103° C. ¹ H-NMR (300MHz, CDCl₃): 4.27 (s, 2H, NH₂) 6.63-6.67 (m, 2H, aromatic) 7.09-7.19 (m,3H, aromatic) 7.68-7.71 (m, 2H, aromatic). MS (CI, CH₄): 234 (M+1).

Analysis for C₁₃ H₉ F₂ NO: Calculated: C, 66.95; H, 3.89; N, 6.01.Found: C, 66.86; H, 4.04; N, 5.95.

EXAMPLE 51N-[4-(2,3-Difluorophenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.02 g, 6.4 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.77 g, 6.4mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4'-Amino-2,3-difluorobenzophenone (1.00 g, 4.3 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The mixture was poured into water and the aqueous solution extractedwith methylene chloride (2×50 mL). The combined organics were washedwith water and 3N HCl (1×50 mL), dried (MgSO₄) and concentrated in vacuoto yield a tan solid. The solid was purified by flash columnchromatography (5% v/v ethyl acetate/methylene chloride).Recrystallization of the resulting solid from methylene chloride/hexaneyielded the title propanamide as a white solid (1.13 g, 70%); mp154°-155° C. ¹ H-NMR (250 MHz, d6-DMSO): 1.60 (s, 3H, CH₃) 7.36-7.40 (m,2H, aromatic) 7.57 (s, 1H, OH) 7.65-7.72 (m, 1H, aromatic) 7.89 (d, 2H,J=8.6 Hz, aromatic) 7.98 (d, 2H, J=8.6 Hz, aromatic) 10.40 (s, 1H, NH).MS (CI, CH₄): 374 (M+1).

Analysis for C₁₇ H₁₂ F₅ NO₃ 0.25 H₂ O: Calculated: C, 54.05; H, 3.33; N,3.70. Found: C, 54.01; H, 3.17; N, 3.68.

The starting benzophenone was made as follows:

a. 4'-Amino-2,3-difluorobenzophenone

To stirred polyphosphoric acid (125 g) heated to 90° C. was added2,3-difluorobenzoic acid (10.00 g, 63.3 mmol) followed by aniline (5.72g, 61.7 mmol). The reaction mixture was heated at 180°-185° C. for 1hour (solid dissolved at 135° C.), then the oil bath was removed anddistilled water (35 mL) was cautiously added in small portions throughthe condenser. The oil bath was returned, and the reaction mixtureheated at 135°-145° C. for 1 hour. The oil bath was again removed, 3NHCl (55 mL) was added to the solution, the reaction mixture was thenpoured into water (750 mL) and stirred for one hour. The aqueoussolution was filtered through Celite and the filtrate basified with 15%NaOH to a pH of 8. A green solid was collected by filtration andpurified by flash column chromatography (methylene chloride).Trituration with hexane yielded the title benzophenone (1.43 g, 10%) asa yellow solid; mp 104°-106° C. ¹ H-NMR (250 MHz, d6-DMSO): 6.41 (s, 2H,NH₂) 6.60 (d, 2H, J=8.7 Hz, aromatic) 7.22-7.37 (m, 2H, aromatic) 7.50(d, 2H, J=8.6 Hz, aromatic) 7.53-7.64 (m, 1H, aromatic). MS (CI, CH₄):234 (M+1).

Analysis for C₁₃ H₉ F₂ NO: Calculated: C, 66.94; H, 3.90; N, 6.00.Found: C, 66.87; H, 3.80; N, 5.91.

EXAMPLE 52N-[4-(2-Cyanophenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.82 g, 5.2 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.62 g, 5.2mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-[(2-Cyanophenyl)sulfonyl]benzeneamine (1.00 g, 3.8 mmol) was added inone portion and the reaction mixture stirred at room temperatureovernight. The mixture was poured-into water and the aqueous solutiondecanted from an oily solid which was purified by flash columnchromatography (5% v/v ethyl acetate/methylene chloride).Recrystallization from methylene chloride/hexane yielded the titlepropanamide as a white solid (1.08 g, 72%); mp 156°-158° C. ¹ H-NMR (250MHz, d6-DMSO): 1.58 (s, 3H, CH₃) 7.59 (s, 1H, OH) 7.88-8.13 (m, 7H,aromatic) 8.31 (d, 1H, J=6.9 Hz, aromatic) 10.50 (s, 1H, OH). MS (CI,CH₄): 399 (M+1).

Analysis for C₁₇ H₁₃ F₃ N₂ O₄ S . 0.50 H₂ O: Calculated: C, 50.12; H,3.46; N, 6.87. Found: C, 49.86; H, 3.17; N, 6.80.

The starting benzeneamine was made as follows:

a. 4-[(2-Cyanophenyl)sulfonyl]benzeneamine

A stirred solution of 2-cyano-4'-nitrodiphenylsulfone (2.54 g, 8.8 mmol)and iron powder (5.39 g, 96.5 mmol) in absolute ethanol (70 mL) washeated to reflux. Ethanolic HCl (0.53 mL concentrated HCl in 20 mL EtOH)was added dropwise over 30 minutes. The reaction mixture was heated atreflux for 4 hours, diluted with absolute ethanol (100 mL) and filteredwhile hot through Celite. The Celite was washed with additional hotethanol (100 mL). The combined ethanol portions were reduced to a volumeof 75 mL and placed in a freezer overnight. The title benzeneamine wascollected by filtration as a white solid (1.81 g, 80%); mp 177°-179° C.¹ H-NMR (300 MHz, d6-DMSO): 6.37 (s, 2H, NH₂) 6.65 (d, 2H, J=8.8 Hz,aromatic) 7.61 (d, 2H, J=8.8 Hz, aromatic) 7.81 (dd, 1H, J=7.5, 1.0 Hz,aromatic) 7.93 (dt, 1H, J=7.6, 1.1 Hz, aromatic) 8.06 (dd, 1H, J=7.5,1.0 Hz, aromatic) 8.17 (d, 1H, J=7.4 Hz, aromatic). MS (CI, CH₄): 259(M+1).

Analysis for C₁₃ H₁₀ N₂ O₂ S . 0.25 H₂ O: Calculated: C, 59.41; H, 3.84;N, 10.66. Found: C, 59.39; H, 3.82; N, 10.60.

b. 2-Cyano-4'-nitrodiphenylsulfone

To a stirred solution of 2-(4-nitrophenylthio)benzonitrile (3.25 g, 12.7mmol) in glacial acetic acid (200 mL) was added potassium permanganate(2.41 g, 15.2 mmol) in distilled water (75 mL). The dark brown mixturewas stirred at room temperature for 1.5 hours, then treated with solidsodium sulfite until the solution clarified. The mixture was dilutedwith water and filtered to yield a tan solid. Recrystallization fromethyl acetate/hexane yielded the title sulfone (2.56 g, 70%) as a whitesolid; mp 172°-174° C. ¹ H-NMR (250 MHz, d6-DMSO): 7.98-8.11 (m, 2H,aromatic) 8.19 (dd, 1H, J=7.1, 1.0 Hz, aromatic) 8.28 (d, 2H, J=8.8 Hz,aromatic) 8.45 (m, 1H, aromatic) 8.49 (d, 2H, J=8.9 Hz, aromatic). MS(CI, CH₄): 289 (M+1).

Analysis for C₁₃ H₈ N₂ O₄ S: Calculated: C, 54.16; H, 2.80; N, 9.72.Found: C, 53.83; H, 2.46; N, 9.63.

c. 2-(4-Nitrophenylthio)benzonitrile

A stirred solution of potassium 4-nitrophenylthiolate (10.61 g, 54.9mmol) and 2-bromobenzonitrile (10.00 g, 54.9 mmol) in dimethylformamide(50 mL) was heated at 95° C. for 22 hours. The reaction mixture waspoured into ice water and a yellow solid was collected by filtration.Purification by flash column chromatography (40% v/v methylenechloride/hexane) followed by recrystallization from 90% ethanol yieldedthe title benzonitrile (3.25 g, 23%) as a yellow solid; mp 151°-153°- C.¹ H-NMR (300 MHz, d6-DMSO): 7.39 (dd, 2H, J=6.9, 2.2 Hz, aromatic)7.73-7.75 (m, 1H, aromatic) 7.81-7.84 (m, 2H, aromatic) 8.08 (dd, 1H,J=7.7, 1.1 Hz, aromatic) 8.19 (dd, 2H, J=6.9, 2.1 Hz, aromatic). MS (CI,CH₄): 257 (M+1).

Analysis for C₁₃ H₈ N₂ O₂ S: Calculated: C, 60.92; H, 3.15; N, 10.83.Found: C, 60.70; H, 3.32; N, 10.99.

EXAMPLE 53N-[3-Hydroxy-4-(phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.78 g, 4.9 mmol) inN,N-dimethylacetamide (10 mL) was added thionyl chloride (0.59 g, 4.9mmol) and the mixture stirred at -10° to -15° C. for 1 hour.4-Amino-2-hydroxybenzophenone (0.70 g, 3.3 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The mixture was poured into water and the aqueous solution decanted froman oily precipitate which was dissolved in methylene chloride, dried(MgSO₄) and concentrated in vacuo to yield a brown oil. Purification byflash column chromatography (5% v/v ethyl acetate/methylene chloride)yielded the title propanamide as a white solid (0.83 g, 71%); mp173°-175° C. ¹ H-NMR (250 MHz, CDCl₃): 1.74 (s, 3H, CH₃) 3.49 (s, 1H,OH) 7.14 (dd, 1H, J=8.7, 2.2 Hz, aromatic) 7.28 (d, 1H, J=2.1 Hz,aromatic),7.46-7.65 (m, 6H, aromatic) 8.49 (s, 1H, NH) 12.3 (s, 1H,phenolic OH). MS (CI, CH₄): (M+1).

Analysis for C₁₆ H₁₄ F₃ NO₄ : Calculated: C, 57.79; H, 3.99; N, 3.96.Found: C, 57.66; H, 4.05; N, 3.95.

4-Amino-2-hydroxybenzophenone is described in B. Arventier, H.Offenberg, Iasi, Sect. I, Chem IIc, (1), 79-85 (1965). (CA 63, 14795d).

EXAMPLE 54N-[4-(3-Fluorophenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.58 g, 10 mmol) inN,N-dimethylacetamide (15 mL) was added thionyl chloride (1.25 g, 10.5mmol) and the mixture stirred at -20° to -10° C. for 1 hour.4-Amino-3'-fluorobenzophenone (1.44 g, 6.7 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The mixture was poured into water to yield an oil and a cloudy solution.The cloudy solution was decanted from the oil and filtered by suctionthrough a pad of Celite. The Celite pad was washed with methylenechloride and the solution added to a solution of the gum in methylenechloride. The solution was dried (MgSO₄), filtered and the solventremoved in vacuo. The resulting oil was chromatographed on silica gel(ethyl ether), the proper fractions combined and the solvent removed toyield an oil. The oil was dissolved in 50 mL of hexane containing enoughmethylene chloride to give a clear solution and the solutionconcentrated on a steambath until the solution became cloudy. Theresulting pale yellow solid was collected by filtration and dried toyield 1.51 g (63%) ofN-[4-(3-fluorophenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylproanamide,mp 121.5°-3° C. ¹ H-NMR (250 MHz, d6-DMSO): 1.59 (s, 3H, CH₃) 3.32 (s,1H, OH) 7.46-7.60 (m, 4H, aromatic) 7.75 (d, 2H, J=9.1 Hz aromatic) 7.96(d, 2H, J=8.2 Hz, aromatic) 10.33 (s, 1H, NH). MS (CI, CH₄): 356 (M+1).

Analysis for C₁₇ H₁₃ F₄ NO₃ : Calculated: C, 57.47; H, 3.69; N, 3.94;Found: C, 57.40; H, 3.65; N, 3.94;

The starting benzaphenone was made as follows:

a. 4-Amino-3'-fluorobenzophenone

To stirred 90° C. polyphosphoric acid (150 g) was added 10.72 g (7.65mmol) of 3-fluorobenzoic acid and 6.98 g (7.5 mmol) of aniline and thebath temperature raised to 180°-190° C. and held there for 1 hour. Asolution was obtained at about 130° C. The heating bath was removed andthe stirred mixture (sublimate above the solution) was treatedcautiously with 60 mL of water. The mixture was stirred at 140°-155° C.for 1 hour, the heating bath removed, 50 mL of 3N HCl added, the mixturepoured into 750 mL of water and filtered through a pad of Celite. Thefiltrate was basified with 15% sodium hydroxide and the resulting solidextracted with methylene chloride. The dried (MgSO₄) solution wasfiltered and the solvent removed to yield a brown solid.Recrystallization from ethanol-hexane (1:3) returned a greenish yellowsolid that was chromatographed on silica gel (methylene chloride) toyield 4.83 g (30%) of yellow 4-amino-3'-fluorobenzophenone, mp 98°-100°C. ¹ H NMR (300 MHz, CDCl₃): 4.21 (s, 2H, NH₂) 6.66-6.70 (m, 2H,aromatic) 7.23-7.26 (m, 1H, aromatic) 7.39-7.51 (m, 3H, aromatic)7.69-7.72 (m, 2H, aromatic). MS (CI, CH₄): 216 (M+1).

Analysis for C₁₃ H₁₀ FNO: Calculated: C, 72.55; H, 4.68; N, 6.51 Found:C, 72.66; H, 4.72; N, 6.25

EXAMPLES 55N-(4-Phenylcarbonyl-3-fluorophenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution of3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.19 g, 7.5 mmol) inN,N-dimethylacetamide (11 mL) was added thionyl chloride (0.92 g, 7.7mmol) and the mixture stirred at -20° to -10° C. for 1 hour.4-Amino-3'-fluorobenzophenone (1.08 g, 5.0 mmol) was added in oneportion and the reaction mixture stirred at room temperature overnight.The mixture was poured into water to yield an oil and a cloudy solution.The cloudy solution was decanted from the oil and filtered by suctionthrough a pad of Celite. The Celite pad was washed with methylenechloride and the solution added to a solution of the gum in methylenechloride. The solution was dried (MgSO₄), filtered and the solventremoved in vacuo. The resulting oil was chromatographed on silica gel.(ethyl ether), the proper fractions combined and the solvent removed toyield a brown oil. The oil was dissolved in 50 mL of hexane containingenough methylene chloride (ca. 25 mL) to give a clear solution and thesolution concentrated on a steambath until the solution became cloudy.The solution was scratched to start crystal growth and an additional 25mL of hexane added. The resulting light tan solid was collected byfiltration and dried to yield 1.43 g (80%) ofN-(4-phenylcarbonyl-3-fluorophenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide, mp 132-4° C. ¹ H-NMR (300 MHz, CDCl₃): 1.78 (s, 3H, CH₃)3.86 (s, 1H, OH) 7.29-7.83 (m, 8H, aromatic) 8.68 (s, 1H, NH). MS (CI,CH₄): 356 (M+1).

Analysis for C₁₇ H₁₃ F₄ NO₃ : Calculated: C, 57.47; H, 3.69; N, 3.94.Found: C, 57.42; H, 3.83; N, 3.91.

The starting benzophenone was made as follows:

a. 4-Amino-2-fluorobenzophenone

To stirred 90° C. polyphosphoric acid (150 g) was added 18.32 g (15.0mmol) of benzoic acid and 8.33 g (7.5 mmol) of 3-fluoroaniline and thebath temperature raised to 220° C. and held there for 1 hour. A solutionwas obtained at about 130° C. The heating bath was removed and thestirred mixture (sublimate above the solution) was treated cautiouslywith 60 mL of water. The mixture was stirred at 140°-155° C. for 1 hour,the heating bath removed, 50 mL of 3N HCl added, the mixture poured into750 mL of water and filtered through a pad of Celite. The filtrate wasbasified with 15% sodium hydroxide and the resulting solid collected.The 1.88 g of solid was chromatographed on silica gel (methylenechloride) to yield 1.15 g (7%) of white fluffy4-amino-2-fluorobenzophenone, mp 133°-5° C. ¹ H NMR (250 MHz, CDCl₃):4.20 (s, 2H, NH₂) 6.33-6.50 (m, 2H, aromatic) 7.27-7.55 (m, 4H,aromatic) 7.76-7.79 (m, 2H, aromatic). MS (CI, CH₄): 216 (M+1).

Analysis for C₁₃ H₁₀ FNO: Calculated: C, 72.55; H, 4.68; N, 6.51 Found:C, 72.20; H, 4.64; N, 6.45

EXAMPLE 56N-[4-(3-Fluorophenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanamide.

To a stirred solution of3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.17 g, 5.5mmol) in dry tetrahydrofuran (35 mL) was added 1,1'-carbonyldiimidazole(0.89 g, 5.5 mmol). The mixture was heated at reflux for 45 minutes,then cooled to room temperature. 4-Amino-3'-fluorobenzophenone (1.08 g,5.0 mmol) was added in one portion and the reaction mixture heated atreflux for 48 hours. Tetrahydrofuran was removed from the reactionmixture in vacuo, and the residue dissolved in ethyl ether and filtered.The filtrate was washed with 3N HCl (50 mL) and water. The ether extractwas dried (MgSO₄) and concentrated in vacuo to an off-white solid.Purification by flash column chromatography (5% v/v ethylether/methylene chloride) yielded the title propanamide as a tan solid(1.13 g, 55%); mp 169°-171° C. ¹ H-NMR (300 MHz, d6-DMSO): 7.50-7.64 (m,4H, aromatic) 7.77-7.82 (m, 2H, aromatic) 7.94-7.98 (m, 2H, aromatic)9.84 (s, 1H, NH) 10.85 (bs, 1H, OH). MS (CI, CH₄): 410 (M+1).

Analysis for C₁₇ H₁₀ F₇ NO₃ : Calculated: C, 49.89; H, 2.46; N, 3.42Found: C, 49.60; H, 2.43; N, 3.34.

EXAMPLE 57N-[4-(2-Fluorophenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanamide.

To a stirred solution of3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.17 g, 5.5mmol) in dry tetrahydrofuran (35 mL) was added 1,1'-carbonyldiimidazole(0.89 g, 5.5 mmol). The mixture was heated at reflux for 45 minutes,then cooled to room temperature. 4-Amino-2'-fluorobenzophenone (1.08 g,5.0 mmol) was added in one portion and the reaction mixture heated atreflux for 48 hours. Tetrahydrofuran was removed from the reactionmixture in vacuo, and the residue dissolved in ethyl ether and filtered.The filtrate was washed with 3N HCl (50 mL) and water. The ether extractwas dried (MgSO₄) and concentrated in vacuo to an off-white solid whichwas purified by flash column chromatography (5% v/v ethylether/methylene chloride). Recrystallization of the resulting solid fromhexane yielded the title propanamide as a tan solid (0.83 g, 40%); mp137°-139° C. ¹ H-NMR (300 MHz, d6-DMSO): 7.36-7.42 (m, 2H, aromatic)7.54-7.60 (m, 1H, aromatic) 7.63-7.69 (m, 1H, aromatic) 7.76-7.79 (m,2H, aromatic) 7.92-7.96 (m, 2H, aromatic) 9.84 (s, 1H, NH) 10.86 (bs,1H, OH). MS (CI, CH₄): 410 (M+1). Analysis for C₁₇ H₁₀ F₇ NO₃ :Calculated: C, 49.89; H, 2.46; N, 3.42. Found: C, 50.05; H, 2.46; N,3.36.

EXAMPLE 58N-[3-Fluoro-4-(phenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanamide.

To a solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoicacid (1.26 g, 5.9 mmol) in dry tetrahydrofuran (35 mL) was added1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol). The mixture was heated to45° C. in an ultrasound bath for 30 minutes, then3-fluoro-4-phenylsulfonylbenzeneamine (1.35 g, 5.4 mmol) was added inone portion. The reaction mixture was heated at 65° C. in the ultrasoundbath for 30 hours. Tetrahydrofuran was removed from the reaction mixturein vacuo, and the residue partitioned between water and ethyl ether. Theaqueous layer was extracted with ethyl ether (2×50 mL), and the combinedether portions were dried (MgSO₄) and concentrated in vacuo to anoff-white solid. The solid was dissolved in ethyl ether, treated withHCl/ethyl ether and filtered to remove unreacted3-fluoro-4-phenylsulfonylbenzeneamine. The filtrate was concentrated invacuo, and the resulting solid recrystallized from ethyl ether/hexane toyield the title propanamide as a white solid (0.32 g, 13%); mp 188°-189°C. ¹ H-NMR (250 MHz, d6-DMSO): 7.62-7.84 (m, 4H, aromatic) 7.91-7.94 (m,3H, aromatic) 8.03-8.09 (m, 2H, aromatic) 9.60 (s, 1H, NH). MS (CI,CH₄): 446 (M+1).

Analysis for C₁₆ H₁₀ F₇ NO₄ S: Calculated: C, 43.16; H, 2.26; N, 3.15.Found: C, 43.17; H, 2.43; N, 3.07.

EXAMPLE 59S-(-)-N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred cooled (0° C.) ofN-[4-(4-pyridylsulfonyl)-phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide(30.86 g, 82 mmol) and triethylamine (13.8 mL, 99 mmol) in dry methylenechloride (500 mL), cooled to 0° C., was added 4-dimethylaminopyridine(catalytic) and S(+)-a-methoxy-α-trifluoromethylphenylacetyl chloride(24.90 g, 99 mmol), the mixture allowed to stir in the ice bath for 30minutes and then at room temperature for 7 hours. The reaction wasdiluted with methylene chloride to a total volume of about 900 mL,treated with water and filtered through a pad of Celite. The organiclayer was separated and the aqueous phase extracted with methylenechloride (2×700 mL). The combined organics was dried (MgSO₄), filteredand the solvent removed to yield a tan foam. The diastereomers wereseparated by repeated flash chromatography (10 v/v ethyl ether inmethylene chloride). The ester (S,S) which eluted second was isolated asa white solid (7.04 g, 15%), mp 159°-160° C. Optical purity of >99% eewas determined by chiral HPLC (Ultron ES OVM column, 12% v/vacetonitrile/KH₂ PO₄ (0.013M, pH 5.5), flow rate: 1 mL/min). ¹ H-NMR(250 MHz, d6-DMSO): 2.12 (s, 3H, CH₃) 3.60 (s, 3H, OCH₃) 7.51-7.60 (m,5H, aromatic) 7.89 (d, 2M, J=2.1 Hz, aromatic) 7.95 (d, 2H, J=8.9 Hz,aromatic) 8.09 (d, 2H, J=3.8 Hz, aromatic) 8.88 (d, 2H, J=5.8 Hz,aromatic) 10.51 (s, 1H, NH). MS (CI CH₄): 591 (M+1). To a stirred,cooled (ice bath) suspension of the (S,S) Mosher ester (7.04 g, 11.9mmol) in methanol (100 mL) was added a solution of sodium hydroxide(0.52 g, 13.1 mmol) in water (10 mL). After the addition of thehydroxide solution the mixture was stirred 15 minutes in the ice bathand an additional 15 minutes with the bath removed. The reaction mixturewas then diluted with water to a final volume of 250 mL, the methanolremoved in vacuo and the white solid collected by filtration and dried.Acidification of the filtrate gave additional material. The combinedyield was 4.25 g (96%), mp 216°-217° C., [α]_(D) ²⁷ =-5.9°, c=1.02 inDMF. Optical purity was established to be >99% ee by chiral HPLC (UltronES OVM column, 12% v/v acetonitrile/KH₂ PO₄ (0.013M, pH 5.5)). Thecompound was determined to be the S configuration by x-raycrystallography. ¹ H-NMR (250 MHz, d6-DMSO): 1.58 (s, 3H, CH₃) 7.61 (s,1H, OH) 7.89 (dd, 2H, J=4.4, 1.5 Hz, aromatic) 8.00 (d, 2H, J=9.0 Hz,aromatic) 8.07 (d, 2H, J=9.0 Hz, aromatic) 8.88 (dd, 2H, J=4.5, 1.7 Hz,aromatic) 10.51 (s, 1H, NH). MS (CI CH₄): 375 (M+1).

Analysis for C₁₅ H₁₃ F₃ N₂ O₄ S: Calculated: C, 48.12; H, 3.51; N, 7.48.Found: C, 48.02; H, 3.57; N, 7.41.

EXAMPLE 60S-(-)-N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a stirred, cooled (-20° C.) solution ofS-(-)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (15.01 g, 94.9mmol) in N,N-dimethylacetamide (225 mL) was added thionyl chloride(11.29 g, 94.9 mmol) dropwise over 5 minutes and the mixture stirred at-10° to -15° C. for one hour. 4-(4-pyridylsulfonyl)aniline (14.82 g,63.2 mmol) was added in one portion to the orange solution and themixture stirred at room temperature overnight. The solution was pouredinto ice water (1 L) and the off-white solid that precipitated wasfiltered from the solution. The solid was dissolved in boiling absoluteethanol (300 mL), allowed to cool to room temperature overnight and thesolid collected. A second crop was recovered after reducing the volumeof the filtrate to 70 mL and allowing the resulting solution to cool toroom temperature. The combined crops were recrystallized from absoluteethanol (150 mL) to yield the title propanamide (17.00 g, 74%) as awhite solid; mp 215°-217° C., [α]_(D) ²⁵ =-5.9°, c=1.025 indimethylformamide. Optical purity was established to be >99% ee bychiral HPLC (Ultron ES OVM column, 12% v/v acetonitrile/KH₂ PO₄ (0.013M, pH 5.5)). (¹ H-NMR (300 MHz, d6-DMSO): 1.71 (s, 3H, CH₃) 7.71 (s, 1H,OH) 8.01 (d, 2H, J=4.5 Hz, aromatic) 8.12 (d, 2H, J=7.1 Hz, aromatic)8.19 (d, 2H, J=7.1 Hz, aromatic) 9.00 (d, 2H, J=4.5 Hz, aromatic) 10.61(s, 1H, NH). MS (CI): 375 (M+1).

Analysis for C₁₅ H₁₃ F₃ N₂ O₄ S: Calculated: C, 48.12; H, 3.51; N, 7.48.Found: C, 48.02; H, 3.59, N, 7.42.

The starting material was made as follows:

a. S-(-)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid

The solvent was removed in vacuo from a solution ofR,S-(±)3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (316.2 g, 3.0mole) and S-(-)-α-methylbenzylamine (363.5 g, 3.0 mole) in ethanol (1.5L), the residue triturated with toluene and the solid collected, washedwith toluene and dried in vacuo. Recrystallization from 10% n-butanol intoluene returned 126.0 g of 97% enantiomerically pure (by ¹⁹ F NMR) S,Ssalt, mp 161°-164° C. The solvent was removed from the recrystallizationliquors and the residue was recrystallized three times from 10%n-butanol in toluene to yield an additional 24.0 g of 97%enantiomerically pure (by ¹⁹ F NMR) S,S salt, mp 162°-165° C. The 150.0g of 97% enantiomerically pure salt was recrystallized twice from 10%n-butanol in toluene to yield 85 g of >99.5% enantiomerically pure (by19F NMR) S,S salt, mp 162.5°-164° C. ¹ H-NMR (300 MHz, CDCl₃): 1.25 (s,3H, CH₃) 1.52 (d, 3H, J=6.8 Hz, CH₃) 4.16 (m, 1H, aliphatic CH)7.25-7.35 (m, 5H, aromatic). [The R,S salt displays the acid CH₃ peak at1.18 ppm and was not evident in this proton spectra]. ¹⁹ F-NMR (376.5MHz, CDCl₃): -79.83. [The R,S salt is shifted downfield by 13 Hz and wasevident in this spectra at a level below the ¹³ C satellite peak(0.5%)]. The liquors from the recrystallization of the 97%enantiomerically pure salt were stripped in vacuo and the residuerecrystallized three times from 10% n-butanol in toluene to yield anadditional 31.5 g of ≧99% enantiomerically pure (by F NMR) S,S salt.

The 85 g of ≧99.5% pure S,S salt was partioned between aqueous HCl (105mL of concentrated HCl and 700 mL of water) and ethyl ether (400 mL).The phases were separated and the aqueous phase was further extractedwith ethyl ether (5×400 mL). The dried extracts (MgSO₄) were filteredand the solvent removed to yield 47.0 g ofS-(-)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid, mp 105°-108° C.,[α]_(D) ²³ =-18.9°, c=9.04 in methanol. ¹ H-NMR (300 MHz, CDCl₃): 1.67(s, CH₃). MS (CI CH₄): 159 (M+1).

Analysis for C₄ H₅ F₃ 0₃ : Calculated: C, 30.39; H, 3.19; Found: C,30.14; H, 3.19.

The 31.5 g of ≧99% pure S,S salt was likewise partioned between aqueousHCl and ethyl ether to yield 17.4 g ofS-(-)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid, mp 107-109° C.,-18.7° , c=4.27 in methanol.

EXAMPLE 61S-(-)-N-(4-Phenylcarbonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.

To a cooled (0° C.), stirred solution ofN-(4-phenylcarbonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide(6.87 g, 20.4 mmol) and triethylamine (3.2 mL, 23 mmol) in methylenechloride (70 mL) was added 4-dimethylaminopyridine (catalytic) followedby the dropwise addition of 1S-(-)-camphanic acid chloride (5.00 g. 23.1mmol). The mixture was stirred at room temperature for 2 hours, dilutedwith methylene chloride (70 mL) and washed with water, 3N HCl (200 mL)and water. The dried (MgSO₄) organics were filtered and the solventremoved in vacuo to yield a white foam. The diastereomers were separatedby repeated flash column chromatography (0 to 3% v/v ethyl ethergradient in methylene chloride). The camphanic ester (S,S) which elutedfirst was isolated as a white foam (3.20 g, 30%). Optical purity of >98%de was determined by chiral HPLC (Chiralcel OD column, 15% v/v ethanolin hexane, flow rate: 1 mL/min). ¹ H-NMR (300 MHz, d6-DMSO): 0.97 (s,3H, CH₃) 1.037 (s, 3H, CH₃) 1.044 (s, 3H, CH₃) 1.58-1.61 (m, 1H,aliphatic) 2.00-2.10 (m, 5H, CH₃, aliphatic) 2.43-2.47 (m, 1H,aliphatic) 7.54-7.59 (m, 2H, aromatic) 7.66-7.82 (m, 7H, aromatic) 10.34(s, 1H, NH). To a suspension of the (S,S) camphanic ester (3.20 g, 6.2mmol) in methanol (40 mL) was added 2N NaOH (3 mL) and the yellowsolution stirred at room temperature for 1 hour. The methanol wasremoved in vacuo, the residue treated with water and the mixtureextracted with methylene chloride (2×50 mL). The dried (MgSO₄) organicswere filtered, the solvent removed in vacuo and the white solidrecrystallized from methylene chloride/hexane to yield 1.80 g (86%) ofS-(-)-N-(4-phenylcarbonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide,mp 171°-3° C., [α]_(D) ²⁷ =-18.8 °, c=1.01 in methanol, opticalpurity: >98% ee by chiral HPLC (Chiralcel OD column, 15% v/v ethanol inhexane, flow rate: 1 mL/min). The compound was determined to have the Sconfiguration by x-ray crystallography. ¹ H-NMR (250 MHz, d6-DMSO): 1.60(s, 3H, CH₃) 7.53-(m, 3H, aromatic, OH) 7.64-7.76 (m, 5H, aromatic) 7.96(d, 2H, J=8.7 Hz, aromatic) 10.33 (s, 1H, NH). MS (CI, CH₄): 338 (M+1).

Analysis for C₁₇ H₁₄ F₃ NO₃ : Calculated: C, 60.54; H, 4.18; N, 4.15.Found: C, 60.49; H, 4.20; N, 4.13.

EXAMPLE 62N-[4-(2-Pyridylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanamide.

Tetrahydrofuran (15 ml, dry) was added to a mixture of2,2-bis-trifluoromethyl-2-hydroxyacetic acid (1.08 g, 5.1 mmol) and1,1'-carbonyldiimidazole (0.83 g, 5.1 mmol) while under a nitrogenatmosphere. There was an immediate evolution of carbon dioxide. Thereaction was placed in an ultrasound bath at 23° C. for 15 min. Thereaction was treated with 4-(2-pyridylcarbonyl)benzeneamine (1.01 g, 5.1mmol), and heated to 43° C. in an ultrasound bath for 48 hr. Theincomplete reaction was treated with a solid mixture of2,2-bis-tri-fluoromethyl-2-hydroxyacetic acid (0.22 g, 1.04 mmol) and1,1'-carbonyldiimidazole (0.20 g, 1.2 mmol) and heated to 53° C. in anultrasound bath for 72 hr. The reaction was evaporated to a gold oil,which was treated with water (100 ml) and extracted with ethyl acetate(2×100 ml) the combined organic portions were dried (MgSO₄) andevaporated to a gold oil. Chromatography of this oil on silica geleluting with methylenechloride/ethyl acetate (first 100:0 and then85:15) provided a tan solid (0.37 g, 19%); mp 197°-200° C. ¹ H-NMR (250MHz, d6-DMSO): 7.68 (m, 1H, ArH), 8.00 (m, 6H, ArH), 8.74 (d, J=4.33,1H, ArH), 9.93 (br s, 1H, OH), 10.83 (br s, 1H, NH). MS(CI,CH₄): 393(M+1).

Analysis for C₁₆ H₁₀ F₆ N₂ O₃ Calculated: C, 48.99; H, 2.57; N, 7.14Found: C, 49.23; H, 2.69; N, 7.33

EXAMPLE 63N-[4-(2-Pyridyl)sulfonylphenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propanamide.

Tetrahydrofuran (5 ml,dry) was added to a mixture of2,2-bis-trifluoromethyl-2-hydroxyacetic acid (0.98 g, 4.6 mmol) and1,1'-carbonyldiimidazole (0.75 g, 4.6 mmol), while under a nitrogenatmosphere. There was an immediate evolution of carbon dioxide. Thereaction was heated at 35° C. in an ultra-sound bath for 15 mins. Thereaction was treated with a solution of4-(2-pyridylsulfonyl)benzeneamine (1.08 g, 4.6 mmol) indimethylformamide (11 mL, dry), heated at 46° C. for 18 hr, and then 60°C. for 24 hr. The incomplete reaction was treated with a solid mixtureof 2,2-bis-trifluoromethyl-2-hydroxy-acetic acid (0.22 g, 1.0 mmol) and1,1'-carbonyldiimidazole (0.20 g, 1.2 mmol), and heated to 52° C. in anultrasound bath for 18 hr. The reaction was evaporated to a viscous goldliquid, which was treated with water (100 ml) and extracted with ethylacetate (2×100 ml). The combined organic portions were dried (MgSO₄) andevaporated to yield a gold oil. Chromatography of this oil on silica geleluting with chloroform/methanol (98:2) provided the title compound(0.37 g, 14%) as a white solid; mp 199°-200° C. ¹ H-NMR (250 MHz,d6-DMSO): 7.70 (m, 1H, ArH), 8.02 (m, 4H, ArH), 8.19 (m, 2H, ArH), 8.71(d, J=4.0 Hz, 1H, ArH), 9.88 (s, 1H, OH), 10.94 (s, 1H, NH). MS(CI,CH₄):429 (M+1)

Analysis for C₁₅ H₁₀ F₆ N₂ O₄ S: Calculated: C, 42.06; H, 2.35. N, 6.53Found: C, 41.99; H, 2.34; N, 6.57

EXAMPLE 64N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propanamide.

Tetrahydrofuran (5 ml,dry) was added to a mixture of2,2-bis-trifluoromethyl-2-hydroxyacetic acid (1.29 g, 6.1 mmol) and1,1'carbonyldiimidazole (0.99 g, 6.1 mmol), while under a nitrogenatmosphere. There was an immediate evolution of carbon dioxide. Thereaction was heated at 35° C. for 15 min. The reaction was treated witha solution of 4-(4-pyridylsulfonyl)benzeneamine (1.43 g, 6.1 mmol) indimethylformamide (15 ml,dry), and heated to 69° C. in an ultrasonicbath for 19.5 hrs. The reaction was poured into water (300 ml), andextracted with ethyl ether (3×300 ml). The combined organic portionswere evaporated and preabsorbed onto silica gel (10 gm). Chromatographyof this material on silica gel, eluting with methylene chloride/ethylacetate (first 100:0 and then 70:30) provided a white solid.Recrystallization from acetone gave starting4-(4-pyridylsulfonyl)benzeneamine. The filtrate was evaporated andchromatographed on silica gel eluting with chloroform/methanol (first100:0 and then 98:2) provided the title compound (0.115 g, 6%) as awhite solid; mp 235°-23° C. ¹ H-NMR (250 MHz, d6-DMSO): 7.90 (d, J=4.6,2H, ArH), 8.04 (d, 4H, ArH)., 8.89 (d, J=4.68 Hz, 2H, ArH), 9.90 (s, 1H,OH), 10.97 (s, 1H, NH). MS(CI,CH₄): 429 (M+1)

Analysis for C₁₅ H₁₀ F₆ N₂ O₄ S: Calculated C, 42.06; H, 2.35; N, 6.53Found: C, 42.11; H, 2.46; N, 6.38

EXAMPLE 65N-[3-(Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethyl-propanamide.

Tetrahydrofuran (15 ml, dry) was added to a mixture of2,2-bis-trifluoromethyl-2-hydroxyacetic acid (0.44 g, 2.1 mmol) and1,1'-carbonyldiimidazole (0.34 g, 2.1 mmol), while under a nitrogenatmosphere. There was an immediate evolution of carbon dioxide. Thereaction was heated to 35° C. in an ultrasound bath for 15 min. Thereaction was treated with 4-(3-pyridylsulfonyl)benzeneamine (0.49 g, 2.1mmol), and heated to 55° C. in an ultrasound bath for 42 hr. Thereaction was evaporated to a viscous yellow oil. Chromatography of thisoil on silica gel eluting with methylene chloride/ethyl acetate (85:15)followed by chromatography of silica gel eluting withchloroform/methanol (98:2) provided the title compound (0.09 g, 10%) asan off-white solid; mp 264°-267° C. ¹ H-NMR (250 MHz, d6-DMSO): 7.68 (m,1H, ArH), 8.03 (m, 4H, ArH), 8.35 (dt, J=8.4, J=1.9 Hz, 1H, ArH), 8.86(dd, J=10.0, J=1.28 Hz, 1H, ArH), 9.13 (d, J=2.35, 1H, ArH), 9.87 (s,1H, OH), 10.94 (s, 1H, NH). MS(CI,CH₄): 429 (M+1)

Analysis for C₁₅ H₁₀ F₆ N₂ O₄ S . 1/2 H₂ O Calculated: C, 41.19; H,2.53; N, 6.41 Found: C, 41.25; H, 2.46; N, 6.19

EXAMPLE 66N-[4-(Phenylcarbonyl)phenyl]-3,3-difluoro-2-hydroxy-2-difluoromethylpropanamide.

To a solution of 2,2,-bis-difluoromethyl-2-hydroxy-acetic acid (1.76 g,10 mmole) in tetrahydrofuran(40 ml) was added carbonyl diimidazole (0.81g, 5 mmole). The flask was placed in a sonic bath and the reactionsonicated for 20 minutes followed by addition of 4-aminobenzophenone.The reaction was sonicated for 18 hours. The reaction mixture wasfiltered and the filtrate evaporated to dryness. The recovered pastysolid was washed with ether and the combined ether washings evaporated.The recovered solid was crystallized from ethyl acetate/hexane to givethe title compound (0.89 g, 25%) as yellow crystals; mp 139°-142° C. ¹H-NMR (300 MHz, d6-DMSO): 6.48(t, J=53.7 Hz, 2H, HCF₂); 7.53-7.77 (m,7H, ArH, OH); 7.95-7.98(m, 3H, ArH); 10.43 (s, 1H, NH). MS(CI,CH₄):356(M+1, 100%).

Analysis for C₁₇ H₁₃ F₄ NO₃ . 0.25 H₂ O Calculated: C, 56.75; H, 3.78;N, 3.89. Found: C, 57.03; H, 3.39; N, 3.84.

EXAMPLE 67N-[4-(2-pyridylsulfonyl)phenyl]-3,3-difluoro-2-hydroxy-2-difluoromethylpropionamide.

To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g,2.84 mmole) in dimethylacetamide (10 ml) at -10° C. was added thionylchloride (0.34 g, 2.84 mmol) dropwise. The resulting solution wasstirred at -10° C. for approximately 30 min.4-(2-Pyridylsulfonyl)aniline (0.58 g, 2.5 mmol) was added and thereaction mixture was stirred overnight at room temperature. The reactionmixture was then poured into water, and sodium bicarbonate solution wasadded to give a pH of 7-7.5. A brown colored precipitate was formed. Thesolid was filtered, washed with water, and dried. Crystallization anddecoloration (charcoal) from ethyl acetate/methanol/hexane gave thetitle compound (0.42 g, 43%) as off-white leaves; mp 200°-202° C. ¹H-NMR(300 MHz, d6-DMSO): 6.45 (t, J=54.09 Hz, 2H, HCF₂), 7.68(t, J=6.24Hz, 1H, ArH), 7.92-8.03 (m, 5H, ArH, OH), 8.11-8.21 (m, 2H, ArH), 8.68(d, J=4.47 Hz, 1H, ArH), 10.54 (s, 1H, NH). MS(CI,CH₄): 393 (M+1, 100%).

Analysis for C₁₅ H₁₂ F₄ N₂ O₄ S: Calculated: C, 45.92; H, 3.08; N, 7.14Found: C, 45.89; H, 3.17; N, 7.12

EXAMPLE 68 N-[4- (Phenylsulfonyl) phenyl]-3,3-di fluoro-2-hydroxy-2-difluoromethyl propionamide.

To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.58, 2.84mmoles) in dimethylacetamide (10 ml) at -10° C. was added thionylchloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution wasstirred at -10° C. for approximately 30 mins. 4-(Phenylsulfonyl) aniline(0.58 g, 2.5 mmoles) was added and the reaction mixture was stirredovernight at room temperature. The reaction mixture was then poured intowater, sodium bicarbonate solution added to give a pH of 7 and extractedwith ethyl acetate. The ethyl acetate extracts were combined, washedwith water, brine, dried (Na₂ SO₄), decolorized (charcoal), andevaporated. The crude solid was dissolved in ether, clarified byfiltration, and evaporated. Crystallization from methanol/water gave thetitle compound (0.56 g, 57%) as white, silky needles; mp 105°-108° C. ¹H-NMR (300 MHz, d6-DMSO) 6.44 (t, J=53.94 Hz, 2H, HCF₂), 7.58-7.68(m,3H, ArH), 7.92°-8.01 (m, 7H, ArH, OH), 10.51 (s, 1H, NH). MS(CI,CH₄):392 (M+1, 100%).

Analysis for C₁₆ H₁₃ F₄ NO₄ S: Calculated: C, 49.11; H, 3.35; N, 3.58.Found: C, 49.15; H, 3.48; N, 3.54

EXAMPLE 69N-[4-(2-Pyridylcarbonyl)phenyl]-3,3-difluoro-2-hydroxy-2-difluoromethylpropionamide.

To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g,2.84 mmoles) in dimethylacetamide (10 mL) at -10° C. was added thionylchloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution wasstirred at -10° C. for approximately 30 mins.4-(2-Pyridylcarbonyl)aniline (0.58 g, 2.5 mmoles) was added and thereaction mixture was stirred overnight at room temperature. The reactionmixture was then poured into water, sodium bicarbonate solution added togive a pH of 7 and extracted with ethyl acetate. The ethyl acetateextracts were combined, washed with water, brine, dried (Na₂ SO₄),decolorized (charcoal), and evaporated. The crude solid was dissolved inether, clarified by filtration, and evaporated to give a yellow orangegum. Crystallization from methylene chloride/hexane gave the titlecompound (0.35 g, 35%) as a tan solid; mp 158°-161° C. ¹ H-NMR (300 MHz,d6-DMSO); 6.48(t, J=54.12 Hz, 2H, HCF₂), 7.67(t, J=6.18 Hz, 1H, ArH),7.91-8.10 (m, 7H, ArH, OH), 8.73 (d, J=7.35 Hz, 1H, ArH), 10.40 (s, 1H,NH). MS(CI),CH₄ : 357(M+H, 100%).

Analysis for C₁₆ H₁₂ F₄ N₂ O₃ : Calculated: C, 53.94; H, 3.39; N, 7.86Found: C, 53.76; H, 3.41; N, 7.87

EXAMPLE 70N-[4-(2-Pyrimidinylsulfonyl)phenyl]-3,3-difluoro-2-hydroxy-2-difluoromethylpropionamide.

To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g,2.84 mmoles) in dimethyl acetamide (10 ml) at -10° C. was added thionylchloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution wasstirred at -10° C. for approximately 30 mins.4-(2-pyrimidylsulfonyl)aniline (0.59 g, 2.5 mmoles) was added and thereaction mixture was stirred overnight at room temperature. The reactionmixture was poured into water, and sodium bicarbonate solution was addedto give a pH of 7-7.5. A dark colored precipitate was formed that wasfiltered, washed with water and dried. The crude material gaspreabsorbed onto silica gel and chromatographed on silica gel elutingwith 70-80% ethyl/acetate/hexane. Evaporation of product-containingfractions and crystallization from methylene chloride/methanol/hexaneEave the title compound (0.33 g, 34%) as a white solid; mp 209°-210° C.¹ H-NMR (300 MHz, d6-DMSO):6.46(t, J=54.06 Hz, 2H, HCF₂), 7.78 (t, J=4.8Hz, 1H, ArH), 7.95-7.98(m, 3H, ArH, OH), 8.02-8.06(m, 2H, ArH), 9.01 (d,J=5.01 Hz, 2H, ArH), 10.58 (s, 1H, NH). MS(CI):394(M+1, 100%).

Analysis for C₁₄ H₁₁ F₄ N₃ O₄ S: Calculated: C, 42.75; H, 2.82; N, 10.68Found: C, 42.55; H, 2.80; N, 10.57

EXAMPLE 71

The following illustrate representative pharmaceutical dosage formscontaining a compound of formula I, for example as illustrated in any ofthe previous Examples, (hereafter referred to as "compound X"), fortherapeutic or prophylactic use in humans:

    ______________________________________                                                                mg/tablet                                             ______________________________________                                        (a)Tablet                                                                     Compound X                50.0                                                Mannitol, USP             223.75                                              Croscarmellose sodium     6.0                                                 Maize starch              15.0                                                Hydroxypropylmethylcellulose (HPMC), USP                                                                2.25                                                Magnesium stearate        3.0                                                 (b)Capsule                                                                    Compound X                10.0                                                Mannitol, USP             488.5                                               Croscarmellose sodium     15.0                                                Magnesium stearate        1.5                                                 ______________________________________                                    

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets may be enteric coated byconventional means, for example to provide a coating of celluloseacetate phthalate. ##STR2##

What is claimed is:
 1. A method of treating asthma comprisingadministering to a mammal in need of such treatment an effective amountof an amide of formula I:wherein: E is selected from nitrogen and CZwherein C is a ring carbon and Z is a substituent defined below,wherein: when E is CZ, X and Z are selected from the group consistingof:(A) X is ArY wherein Y is a linking group selected from carbonyl,sulfinyl, and sulfonyl and Ar is selected from the group consistingof:phenyl substituted with 0-2 substituents selected from halo, hydroxy,cyano, (1-4C)alkyl, and (1-4C)alkoxy, provided that the 4-position ofsaid phenyl may be substituted by fluoro only, and that the said phenylmay not be 3,5-disubstituted; six-membered heteroaryl rings containing1-2 nitrogen atoms as the only heteroatoms; five-membered heteroarylrings containing from 1-2 heteroatoms selected from nitrogen, oxygen,and sulfur; provided that Ar is not 3-chlorophenyl, 3-bromophenyl,3-iodophenyl, 3-(1-4C)alkylphenyl, or 4-pyridyl when Y is carbonyl, andthat Ar is not 5-pyrimidinyl when Y is sulfonyl or carbonyl; and Z isselected from hydrogen, cyano, halo, hydroxy, (1-4C)alkyl, and(1-4C)alkoxy; (B) X is cyano and Z is selected from the group consistingof phenylthio, phenylsulfinyl, and phenylsulfonyl the phenyl rings ofwhich are substituted with 0-2 substituents selected from halo, hydroxy,cyano, nitro, (1-4C)alkyl, and (1-4C)alkoxy; when E is nitrogen, X isindependently selected from any of the values for X given above in (A);R² and R³ are independently selected from the group consisting of(1-3C)alkyl substituted by from 0 to 2k+1 groups selected from fluoroand chloro wherein k is the number of carbon atoms in the said(1-3C)alkyl, provided that R² and R³ are not both methyl; or together,with the carbon atom to which both R² and R³ are attached, form a 3-5membered cycloalkyl ring optionally substituted by from 0 to 2m-2 fluorogroups wherein m is the number of carbon atoms in said ring; or apharmaceutically acceptable in vivo hydrolyzable ester of said amide;ora pharmaceutically acceptable salt of said amide or said ester.
 2. Amethod of treating asthma as claimed in claim 1 wherein said amide offormula I is an amide of formula Id: ##STR3## wherein: X and Z areselected from the group consisting of:(A) X is ArY whereinY is a linkinggroup selected from carbonyl, sulfinyl, and sulfonyl and Ar is selectedfrom the group consisting of phenyl, 2-, 3- and 4-fluorophenyl, 2- and3-chlorophenyl, 2- and 3-cyanophenyl, 2- and 3-hydroxyphenyl, 2- and3-methoxyphenyl, 2- and 3-methylphenyl, 2-, 3- and 4-pyridyl, 2- and4-pyrimidinyl, 3- and 4-isothiazolyl, 2- and 4-oxazolyl, 2- and4-thiazolyl, 2- and 3-furyl, and 2- and 3-thienyl; Z is selected fromhydrogen, cyano, halo, hydroxy, (1-2C)alkyl, and (1-2C)alkoxy; (B) X isCN, Z is phenylsulfonyl; R² and R³ are independently selected from thegroup consisting of (1-3C)alkyl substituted by from 0 to 2k+1 fluorogroups wherein k is the number of carbon atoms in the said (1-3C)alkyl,provided that R² and R³ are not both methyl.
 3. A method of treatingasthma as claimed in claim 2 whereinX is ArY and wherein Ar, Y, and Zare selected from the group consisting of:(i) Y is sulfonyl, Z ishydrogen, and Ar is selected from the group consisting of:phenylsubstituted with 0-1 substitutents, selected from phenyl, 2-, 3-, and4-fluorophenyl, 2- and 3-chlorophenyl, 2- and 3-methoxyphenyl, 2- and3-cyanophenyl, 2- and 3-hydroxyphenyl, and 2- and 3-methylphenyl;six-membered heteroaryl rings selected from 2-, 3- and 4-pyridyl, and2-pyrimidinyl; five-membered heteroaryl rings selected from 2-thienyland 2-thiazolyl; (ii) Y is sulfonyl, Ar is phenyl or 4-pyridyl, and Z isselected from the group consisting of cyano, fluoro, hydroxy, methoxyand methyl; and (iii) Y is carbonyl, Z is hydrogen, and Ar is selectedfrom the group consisting of phenyl and 2-pyridyl; and R² and R³ areindependently selected from the group consisting of (i) R² istrifluoromethyl and R³ is selected from methyl, ethyl, andtrifluoromethyl; and (ii) R² is difluoromethyl and R³ is difluoromethyl.4. A method of treating asthma as claimed in claim 1 wherein said amideis selectedfrom;N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propanamide;S-(-)-N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;S-(-)-N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;N-[4-(4-Pyridylsulfonyl)phenyl]-3,3-difluoro-2-hydroxy-2-difluoromethylpropanamide;N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethylmethylpropanamide;N-[4-(4-Pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanamide;orN-[3-Hydroxy-4-(4=pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.5. A method of treating asthma as claimed in claim 4 wherein said amideis:N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide;orS-(-)-N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.6. A method of treating asthma as claimed in claim 5 wherein said amideisS-(-)-N-[4-(Phenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.